2023 Research Investment
Blood Cancer Discoveries Grant
The Blood Cancer Discoveries Grant Program, in partnership with the Leukemia & Lymphoma Society (US), provides funding for Blood Cancer Discoveries Grant Program to Canadian researchers. It supports cutting edge, innovative research that is discovery oriented, concerned with understanding blood cancer properties and vulnerabilities and aimed toward advancing treatments for blood cancers. This program is intended for established academic investigators for support of foundational, early-stage research that can lead to advances in the treatment and cure of blood cancers.
Dr. Courtney Jones
Princess Margaret Cancer Centre, Toronto
Interrogation of glutathione biology in relapsed acute myeloid leukemia stem cells
Most acute myeloid leukemia (AML) patients who receive therapy will respond, however, their leukemia usually returns. Consequently, there is an urgent need to develop new therapies for relapsed patients.
Preliminary findings from Dr. Jones’ research team show that relapsed AML cells are dependent on a molecule called glutathione (GSH), which changes the function within these cells. Importantly, inhibiting GSH does not affect normal blood cells, suggesting it could be a target for a new AML therapy with limited side effects.
In this project, the research team aims to understand and target properties specific to relapsed AML cells, which will enable the discovery of new therapeutic targets for relapsed AML patients.
Most acute myeloid leukemia (AML) patients who receive therapy will respond, however, their leukemia usually returns. Consequently, there is an urgent need to develop new therapies for relapsed patients.
Preliminary findings from Dr. Jones’ research team show that relapsed AML cells are dependent on a molecule called glutathione (GSH), which changes the function within these cells. Importantly, inhibiting GSH does not affect normal blood cells, suggesting it could be a target for a new AML therapy with limited side effects.
In this project, the research team aims to understand and target properties specific to relapsed AML cells, which will enable the discovery of new therapeutic targets for relapsed AML patients.
Operating Grants
The LLSC is pleased to partner with Cancer Research Society to co-fund ten (10) blood cancer projects from the CRS 2022 Operating Grant Competition.
The grants that focus on advancing the understanding of and improving treatment options for all blood cancers.
Dr. Fawzi Aoudjit
Laval University, Quebec City
Uncovering the mechanisms of cell adhesion-induced chemoresistance in T cell acute lymphoblastic leukemia (T-ALL)
T cell-acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of all childhood leukemia and 25% of all adult leukemia. Although chemotherapy has improved the treatment of T-ALL, especially in children, resistance to chemotherapy is a major factor in patient relapse and is associated with poor outcome and with significant fatalities. Therefore, a better understanding of how leukemic T-ALL cells manage to escape chemotherapy and become resistant will likely lead to more effective therapies.
Our team has recently identified a molecule called GPR52 expressed in leukemic T-ALL cells, and which can be a critical factor in the resistance of these cells to chemotherapy. When we blocked this molecule, we were able to destroy leukemic cells with chemotherapy with greater success. In this proposal, we will characterize the implication of GPR52 in the development of drug resistance of leukemic T-ALL cells and examine the mechanisms by which it does so. We will also determine if blocking GPR52 can be effective in eradicating leukemic T-ALL cells from patients who have received chemotherapy. These studies have the potential of revealing a novel therapeutic target in T-ALL. Accordingly, inhibition of GPR52 with existing inhibitors combined with chemotherapy may be a novel strategy for T-ALL therapy to improve chemotherapy, lower toxicity and help prevent patient relapse.
T cell-acute lymphoblastic leukemia (T-ALL) accounts for approximately 15% of all childhood leukemia and 25% of all adult leukemia. Although chemotherapy has improved the treatment of T-ALL, especially in children, resistance to chemotherapy is a major factor in patient relapse and is associated with poor outcome and with significant fatalities. Therefore, a better understanding of how leukemic T-ALL cells manage to escape chemotherapy and become resistant will likely lead to more effective therapies.
Our team has recently identified a molecule called GPR52 expressed in leukemic T-ALL cells, and which can be a critical factor in the resistance of these cells to chemotherapy. When we blocked this molecule, we were able to destroy leukemic cells with chemotherapy with greater success. In this proposal, we will characterize the implication of GPR52 in the development of drug resistance of leukemic T-ALL cells and examine the mechanisms by which it does so. We will also determine if blocking GPR52 can be effective in eradicating leukemic T-ALL cells from patients who have received chemotherapy. These studies have the potential of revealing a novel therapeutic target in T-ALL. Accordingly, inhibition of GPR52 with existing inhibitors combined with chemotherapy may be a novel strategy for T-ALL therapy to improve chemotherapy, lower toxicity and help prevent patient relapse.
Dr. Nicolas Bertrand
Laval University, Quebec City
Anti-PEG antibodies and adverse reactions to PEGylated drugs: effect of mRNA vaccination and novel mitigation strategies.
Acute lymphoblastic leukemia (ALL) is a blood cancer that occurs mostly in children. Although the prognosis is generally good, the treatment causes cumulative adverse reactions significantly affecting the quality of life of these young patients.
PEGylated asparaginase (PEG-ASNase) is a key drug used in the management of ALL. This drug is a bacterial protein that has been modified by attaching poly(ethylene glycol) (PEG), a synthetic polymer. A problem with PEG-ASNase is that some patients can develop antibodies that decrease the effectiveness of the drug while increasing adverse reactions. Some of these antibodies recognize the PEG on the protein.
PEG is very broadly used in the pharmaceutical and cosmetic industries, including in mRNA vaccines used to protect against COVID-19. This means that some people might develop anti-PEG antibodies before even receiving PEG-ASNase.
The mechanisms behind the production of PEG-recognizing antibodies are not well understood. This research project will explore how PEG-ASNase triggers the production of anti-PEG antibodies and evaluate how the drug cross reacts with pre-existing anti-PEG antibodies. In parallel, we will also fabricate a next generation of PEG-ASNase that does not have the limitations of the current treatment. Altogether, this project will lead to a better management of ALL patients with pre-existing anti-PEG antibodies and will contribute to the development of a novel class of safer therapies.
Acute lymphoblastic leukemia (ALL) is a blood cancer that occurs mostly in children. Although the prognosis is generally good, the treatment causes cumulative adverse reactions significantly affecting the quality of life of these young patients.
PEGylated asparaginase (PEG-ASNase) is a key drug used in the management of ALL. This drug is a bacterial protein that has been modified by attaching poly(ethylene glycol) (PEG), a synthetic polymer. A problem with PEG-ASNase is that some patients can develop antibodies that decrease the effectiveness of the drug while increasing adverse reactions. Some of these antibodies recognize the PEG on the protein.
PEG is very broadly used in the pharmaceutical and cosmetic industries, including in mRNA vaccines used to protect against COVID-19. This means that some people might develop anti-PEG antibodies before even receiving PEG-ASNase.
The mechanisms behind the production of PEG-recognizing antibodies are not well understood. This research project will explore how PEG-ASNase triggers the production of anti-PEG antibodies and evaluate how the drug cross reacts with pre-existing anti-PEG antibodies. In parallel, we will also fabricate a next generation of PEG-ASNase that does not have the limitations of the current treatment. Altogether, this project will lead to a better management of ALL patients with pre-existing anti-PEG antibodies and will contribute to the development of a novel class of safer therapies.
Dr. Shokrollah Elahi
University of Alberta, Edmonton
IL-16 as a novel therapeutic target in hematological cancers
Killer T-cells are a critical part of the immune system which fight cancers. This protection is achieved by the killer T-cells’ ability to target and kill tumour cells. However, the cancer-killing capabilities of killer T-cells can be progressively reduced, commonly referred to as killer T-cell exhaustion. Exhausted killer T-cells display special proteins on their surface that prevent their ability to kill tumour cells.
Recently, we discovered a special protein, called CD160, on the surface of killer T cells in the blood and bone marrow of patients with chronic lymphocytic leukemia (CLL). We found that malignant cells in CLL patients are constantly secreting another protein (IL-16) which is responsible for the increased presence of CD160. The presence of CD160 acts like a break on the immune system. Finally, we noted that a higher presence of IL-16 was associated with poor prognosis in CLL patients.
Therefore, we propose conducting further studies on a larger group of patients to reconfirm our previous observations. We will also use a model of CLL to investigate the potential of targeting this secreted protein (IL-16) by malignant cells as a therapeutic approach. We believe our studies will enable us to propose a potential and novel immunotherapy target in CLL and possibly other blood cancers.
Killer T-cells are a critical part of the immune system which fight cancers. This protection is achieved by the killer T-cells’ ability to target and kill tumour cells. However, the cancer-killing capabilities of killer T-cells can be progressively reduced, commonly referred to as killer T-cell exhaustion. Exhausted killer T-cells display special proteins on their surface that prevent their ability to kill tumour cells.
Recently, we discovered a special protein, called CD160, on the surface of killer T cells in the blood and bone marrow of patients with chronic lymphocytic leukemia (CLL). We found that malignant cells in CLL patients are constantly secreting another protein (IL-16) which is responsible for the increased presence of CD160. The presence of CD160 acts like a break on the immune system. Finally, we noted that a higher presence of IL-16 was associated with poor prognosis in CLL patients.
Therefore, we propose conducting further studies on a larger group of patients to reconfirm our previous observations. We will also use a model of CLL to investigate the potential of targeting this secreted protein (IL-16) by malignant cells as a therapeutic approach. We believe our studies will enable us to propose a potential and novel immunotherapy target in CLL and possibly other blood cancers.
Dr. Kristin Hope
University Health Network, Toronto
Targeting the epigenetic reader MBD1 as a novel strategy to intercept acute myeloid leukemia
Acute myeloid leukemia (AML) has a five-year survival rate of 21%. AML is difficult to treat because when diagnosed, the disease has already become complex and aggressive. The disease is sustained by cancer driving blood stem cells, which have acquired many extra mutations beyond the original ones that first led to the early disease or “pre-leukemia”.
Consequently, targeted treatment against these few early genetic changes prior to AML is crucial. It is our goal is to study the pre-leukemic disease myelodysplastic syndrome (MDS) to uncover these key factors.
One process which may promote pre-leukemic blood stem cell development is alternative splicing, which can lead to the production of different proteins from the same genetic information. We have found that changes in how the protein MBD1 is spliced may create and maintain the MDS disease state.
The research team will map pre-leukemic changes stimulated by incorrectly spliced MBD1 and test the therapeutic potential of depleting it in patient MDS cells. We will also establish the biological changes stimulated by incorrectly spliced MBD1 to identify processes that might respond to treatment with drugs.
Though critical to early intervention and prevention of AML, our knowledge of therapeutic targets in early MDS/AML development are limited. Identification of alternatively spliced MBD1 as a key initiating factor will give crucial insights into pre-leukemic biomarkers and treatable pathways, providing great promise for early AML diagnosis and intervention.
Acute myeloid leukemia (AML) has a five-year survival rate of 21%. AML is difficult to treat because when diagnosed, the disease has already become complex and aggressive. The disease is sustained by cancer driving blood stem cells, which have acquired many extra mutations beyond the original ones that first led to the early disease or “pre-leukemia”.
Consequently, targeted treatment against these few early genetic changes prior to AML is crucial. It is our goal is to study the pre-leukemic disease myelodysplastic syndrome (MDS) to uncover these key factors.
One process which may promote pre-leukemic blood stem cell development is alternative splicing, which can lead to the production of different proteins from the same genetic information. We have found that changes in how the protein MBD1 is spliced may create and maintain the MDS disease state.
The research team will map pre-leukemic changes stimulated by incorrectly spliced MBD1 and test the therapeutic potential of depleting it in patient MDS cells. We will also establish the biological changes stimulated by incorrectly spliced MBD1 to identify processes that might respond to treatment with drugs.
Though critical to early intervention and prevention of AML, our knowledge of therapeutic targets in early MDS/AML development are limited. Identification of alternatively spliced MBD1 as a key initiating factor will give crucial insights into pre-leukemic biomarkers and treatable pathways, providing great promise for early AML diagnosis and intervention.
Dr. Robert Kridel
University Health Network, Toronto
Elucidation of the Immune Contexture and Gene Regulatory Basis Underlying Post-Transplant Lymphoproliferative Disorders
The transplantation of an organ is a critical point in the life of patients who live with failing organs. For example, an organ transplantation can eliminate the need for dialysis for patients with end-stage kidney disease, or hopefully prevent death from terminal lung or heart conditions.
Unfortunately, an organ transplantation is accompanied by the requirement for life-long immunosuppressive treatment, which comes at the cost of health complications, including infections and an increased risk of malignancies. Of particular importance is the abnormal growth of tumours that arise from a specific type of white blood cells, known as lymphocytes. This growth is referred to as Post-Transplant Lymphoproliferative Disorder (PTLD).
The development of PTLD is a serious condition that carries a risk of early death. Moreover, patients may require toxic chemotherapy, which is often poorly tolerated due to comorbidities and pre-existing immune suppression. Consequently, there is a compelling need for better therapies for PTLD.
Unfortunately, the nature of PTLD is not well understood. In this proposal, we will perform an in-depth analysis of the composition of PTLD tumour samples, using a novel high-resolution technology which allows us to study these samples one cell at a time. We will uncover the biological underpinnings of this uncommon condition, which will unlock the potential to design novel therapeutic approaches.
The transplantation of an organ is a critical point in the life of patients who live with failing organs. For example, an organ transplantation can eliminate the need for dialysis for patients with end-stage kidney disease, or hopefully prevent death from terminal lung or heart conditions.
Unfortunately, an organ transplantation is accompanied by the requirement for life-long immunosuppressive treatment, which comes at the cost of health complications, including infections and an increased risk of malignancies. Of particular importance is the abnormal growth of tumours that arise from a specific type of white blood cells, known as lymphocytes. This growth is referred to as Post-Transplant Lymphoproliferative Disorder (PTLD).
The development of PTLD is a serious condition that carries a risk of early death. Moreover, patients may require toxic chemotherapy, which is often poorly tolerated due to comorbidities and pre-existing immune suppression. Consequently, there is a compelling need for better therapies for PTLD.
Unfortunately, the nature of PTLD is not well understood. In this proposal, we will perform an in-depth analysis of the composition of PTLD tumour samples, using a novel high-resolution technology which allows us to study these samples one cell at a time. We will uncover the biological underpinnings of this uncommon condition, which will unlock the potential to design novel therapeutic approaches.
Dr. Moutih Rafei
Université de Montréal
Optimizing the anti-tumoral potency of the MSC-TPr vaccine
Although most cancer vaccines based on the use of dendritic cells – type of immune cell - rely exclusively on the degradation of antigens by the immunoproteasome complex, the functional contribution of the thymoproteasome (TPr) to immunity remains unclear. We therefore explored whether mesenchymal stromal cells (MSCs) could behave as antigen-presenting cells following de novo expression of the TPr complex. Once confirmed for their ability to process and present peptides derived from soluble exogenous proteins, we next tested their protective efficacy against lymphoma and found that they can indeed trigger anti-tumoral responses. However, their mode of action remains unclear and involves an interplay with two important endogenous immune cells. The aim this study is to better understand how the MSCTPr cells rely on endogenous third parties to induce an immune response in order to develop new and more effective anti-lymphoma vaccine for cancer patients.
Although most cancer vaccines based on the use of dendritic cells – type of immune cell - rely exclusively on the degradation of antigens by the immunoproteasome complex, the functional contribution of the thymoproteasome (TPr) to immunity remains unclear. We therefore explored whether mesenchymal stromal cells (MSCs) could behave as antigen-presenting cells following de novo expression of the TPr complex. Once confirmed for their ability to process and present peptides derived from soluble exogenous proteins, we next tested their protective efficacy against lymphoma and found that they can indeed trigger anti-tumoral responses. However, their mode of action remains unclear and involves an interplay with two important endogenous immune cells. The aim this study is to better understand how the MSCTPr cells rely on endogenous third parties to induce an immune response in order to develop new and more effective anti-lymphoma vaccine for cancer patients.
Dr. Anthony Rullo
McMaster University, Faculty of Health Sciences, Hamilton
Tumour Targeting of Universal T cells Using Covalent Adapter Molecules
White blood cells can recognize and destroy tumour tissue. However, the white blood cells in cancer patients lose their ability to recognize tumours. We have developed methods, using genetic engineering, to restore the ability of the cancer patient's white blood cells to attack their tumours.
While our current method is effective, the manufacturing process is expensive and time consuming, which limits the accessibility of this promising therapy. To increase accessibility and reduce cost, we are developing white blood cells that can be delivered through hospital pharmacies, directly off the shelf. However, the programming of the white blood cells to attack cancerous tumours remains a challenge.
In this project, we will improve the engineering methods used to produce the off-the-shelf white blood cells and develop novel chemical methods to program the white blood cells to attack the cancer. Through these efforts, we aim to develop a flexible and dynamic therapy that can be used broadly to treat many cancers.
White blood cells can recognize and destroy tumour tissue. However, the white blood cells in cancer patients lose their ability to recognize tumours. We have developed methods, using genetic engineering, to restore the ability of the cancer patient's white blood cells to attack their tumours.
While our current method is effective, the manufacturing process is expensive and time consuming, which limits the accessibility of this promising therapy. To increase accessibility and reduce cost, we are developing white blood cells that can be delivered through hospital pharmacies, directly off the shelf. However, the programming of the white blood cells to attack cancerous tumours remains a challenge.
In this project, we will improve the engineering methods used to produce the off-the-shelf white blood cells and develop novel chemical methods to program the white blood cells to attack the cancer. Through these efforts, we aim to develop a flexible and dynamic therapy that can be used broadly to treat many cancers.
Dr. Woong-Kyung Suh
Montreal Clinical Research Institute
Epigenetic driving forces of angioimmunoblastic T cell lymphoma (AITL)
AITL is an aggressive T cell lymphoma originating from normal “helper T cells” that defend our body from pathogens. Chemotherapy is the only treatment for AITL but it remains inadequate. As a result, we need more precise and powerful drugs to cure this disease.
Our research team recently invented ways to distinguish malignant tumour cells from normal helper T cells residing in the tumour. Importantly, the research team has collected evidence that these malignant tumour cells rely on an enzyme termed “EZH2” that dictates what type of genes should be turned on or off. Using research models of AITL, we will study how EZH2 promotes growth of AITL tumour cells and what genes are involved in this process. If successful, our study will uncover promising therapeutic targets to treat AITL patients.
AITL is an aggressive T cell lymphoma originating from normal “helper T cells” that defend our body from pathogens. Chemotherapy is the only treatment for AITL but it remains inadequate. As a result, we need more precise and powerful drugs to cure this disease.
Our research team recently invented ways to distinguish malignant tumour cells from normal helper T cells residing in the tumour. Importantly, the research team has collected evidence that these malignant tumour cells rely on an enzyme termed “EZH2” that dictates what type of genes should be turned on or off. Using research models of AITL, we will study how EZH2 promotes growth of AITL tumour cells and what genes are involved in this process. If successful, our study will uncover promising therapeutic targets to treat AITL patients.
Dr. Anastasia Tikhonova
University Health Network, Toronto
Targeting the molecular interaction of acute lymphoblastic leukemia with the bone marrow microenvironment
Acute leukemias are a collection of aggressive and devastating blood cancers. Despite improvements in treatment, relapse is frequent and inevitably leads to death.
Recent advancements indicate that blood cancers depend on specialized “support cells” in the bone marrow. However, it is not known if blocking the interactions between blood cancers and their support system can improve treatment for these blood malignancies.
Using cutting edge technology, this project will study the effects of removing blood cancer cells from their supportive environment on leukemic progression and relapse. The researchers envision that these studies will fundamentally lead to new therapies targeting these devastating cancers and ultimately improve patient outcomes.
Acute leukemias are a collection of aggressive and devastating blood cancers. Despite improvements in treatment, relapse is frequent and inevitably leads to death.
Recent advancements indicate that blood cancers depend on specialized “support cells” in the bone marrow. However, it is not known if blocking the interactions between blood cancers and their support system can improve treatment for these blood malignancies.
Using cutting edge technology, this project will study the effects of removing blood cancer cells from their supportive environment on leukemic progression and relapse. The researchers envision that these studies will fundamentally lead to new therapies targeting these devastating cancers and ultimately improve patient outcomes.
Dr. Zhaolei Zhang
University of Toronto
Single cell proteo-genomics integrating mutation profiles with protein signatures to identify relapse-fated leukemic clones in FLT3-ITD AML
Every year, AML affects one million people worldwide, resulting in 150,000 deaths. About 25 to 30% of AML patients have a mutation in the gene FLT3. Such mutations, called FLT3-ITD, typically result in an extremely high risk of relapse among AML patients.
Currently, the standard method to assess FLT3-ITD in patients is by using a laboratory technique called Polymerase Chain Reaction (PCR). However, because tumours are usually composed of a diverse population of cells with different genetic makeups , PCR can only obtain genetic information of all the cells in aggregate and cannot provide exact information on individual cells.
Such ambiguity can cause inaccurate prognosis or even prevent the identification of the best treatment options. To address these issues, our research team has decided to use state-of-the-art single cell sequencing technology to determine the exact genetic makeup of every single cell. This new technology can also measure the abundance of specific protein markers on the cell surface and provides additional information on these tumour cells. It has the promise of precisely defining tumour cell lineages during tumour progression and helping to improve prognosis and selection of optimal treatment.
Every year, AML affects one million people worldwide, resulting in 150,000 deaths. About 25 to 30% of AML patients have a mutation in the gene FLT3. Such mutations, called FLT3-ITD, typically result in an extremely high risk of relapse among AML patients.
Currently, the standard method to assess FLT3-ITD in patients is by using a laboratory technique called Polymerase Chain Reaction (PCR). However, because tumours are usually composed of a diverse population of cells with different genetic makeups , PCR can only obtain genetic information of all the cells in aggregate and cannot provide exact information on individual cells.
Such ambiguity can cause inaccurate prognosis or even prevent the identification of the best treatment options. To address these issues, our research team has decided to use state-of-the-art single cell sequencing technology to determine the exact genetic makeup of every single cell. This new technology can also measure the abundance of specific protein markers on the cell surface and provides additional information on these tumour cells. It has the promise of precisely defining tumour cell lineages during tumour progression and helping to improve prognosis and selection of optimal treatment.
Translational Research Program Grants
In partnership with the Leukemia & Lymphoma Society (US), we are funding Translational Research Program (TRP) grants to put researchers on the bench-to-bedside fast track when it comes to finding better treatments and cures for blood cancers. Through this program, we are funding new and innovative research that shows high promise for translating basic biomedical knowledge to an application that can help those affected by a blood cancer.
Dr. Kirk Schultz
BC Children’s Hospital Research Institute, Vancouver
Polyomic Approach to Chronic Graft vs. Host Disease Biomarkers in Adults
While bone marrow transplantation can successfully treat and even cure blood cancers, its use is still limited because of the risk of a life-threatening, autoimmune complication called chronic graft-versus-host disease (cGvHD). This complication occurs when the donor immune system attacks healthy tissues in the recipient.
Using the expertise and data collected through the Canada-based Applied Biomarkers in Late Effects of Children and Adolescents with Cancer (ABLE) team, the research team will determine how well the pediatric cGvHD risk predictor and diagnostic classifier can be used with adult hematopoietic stem cell transplant (HSCT) data (ages 18 to 60 years).
The research team will use a multi-faceted approach to understand what leads to cGvHD in this adult population and, ultimately, decrease its occurrence.
While bone marrow transplantation can successfully treat and even cure blood cancers, its use is still limited because of the risk of a life-threatening, autoimmune complication called chronic graft-versus-host disease (cGvHD). This complication occurs when the donor immune system attacks healthy tissues in the recipient.
Using the expertise and data collected through the Canada-based Applied Biomarkers in Late Effects of Children and Adolescents with Cancer (ABLE) team, the research team will determine how well the pediatric cGvHD risk predictor and diagnostic classifier can be used with adult hematopoietic stem cell transplant (HSCT) data (ages 18 to 60 years).
The research team will use a multi-faceted approach to understand what leads to cGvHD in this adult population and, ultimately, decrease its occurrence.
Dr. Christian Steidl
BC Cancer, Vancouver
Targeting aberrant non-canonical NF-κB pathway activation in B-cell lymphomas
B-cell lymphomas are the largest group of newly diagnosed blood cancers in North America. Despite significant improvements in treatment, a significant proportion of patients experience relapsed or refractory disease. Developing more effective and personalized treatments is, therefore, a pressing unmet need.
Dr. Steidl’s research team has found that genetic alterations in a pathway that regulates important aspects of the body’s immune function – the non-canonical NF-kB pathway – is found a many B-cell lymphomas. The finding suggests that these alterations could be targeted with new therapies.
In this project, the research team will identify the genetic mutations related to the pathway, define the weaknesses in the pathway and test combination immunotherapies.
B-cell lymphomas are the largest group of newly diagnosed blood cancers in North America. Despite significant improvements in treatment, a significant proportion of patients experience relapsed or refractory disease. Developing more effective and personalized treatments is, therefore, a pressing unmet need.
Dr. Steidl’s research team has found that genetic alterations in a pathway that regulates important aspects of the body’s immune function – the non-canonical NF-kB pathway – is found a many B-cell lymphomas. The finding suggests that these alterations could be targeted with new therapies.
In this project, the research team will identify the genetic mutations related to the pathway, define the weaknesses in the pathway and test combination immunotherapies.
2022 Research Investment
Jump Start Grants
The COVID-19 pandemic affected researchers’ capacity to conduct their regular research and training activities. These one-time grants will provide a boost to blood cancer research that was stalled because of the pandemic.
Dr. Jason Berman
Children's Hospital of Eastern Ontario Research Institute, Ottawa
Breaking the KMT2C:KMT2A-r alliance in rapid-onset infant leukemia
Infant leukemia occurs in children less than one year of age and has poor survival rates due primarily due to the toxicity of current treatments. Infant leukemia is frequently the result of abnormalities in the lysine methyltransferase 2A (KMT2A) gene that is present on chromosome 11. The chromosome breaks at the region containing KMT2A and joins to genes (MLLT3 and MLLT1) on other chromosomes resulting in fusions. SomeKMT2A fusions with additional mutations in the gene lysine methyltransferase 2C (KMT2C) lead to a more rapid development of the disease.
For this study, the research team will use zebrafish models that have mutations in the zebrafish KMT2A gene and study whether either the KMT2A-MLLT3 or KMT2A-MLLT1 fusion impacts blood development and speeds up development of leukemia. The researchers will carry out drug screens targeting key disease pathways to identify potential new effective and safe treatments for this vulnerable group of patients.
Infant leukemia occurs in children less than one year of age and has poor survival rates due primarily due to the toxicity of current treatments. Infant leukemia is frequently the result of abnormalities in the lysine methyltransferase 2A (KMT2A) gene that is present on chromosome 11. The chromosome breaks at the region containing KMT2A and joins to genes (MLLT3 and MLLT1) on other chromosomes resulting in fusions. SomeKMT2A fusions with additional mutations in the gene lysine methyltransferase 2C (KMT2C) lead to a more rapid development of the disease.
For this study, the research team will use zebrafish models that have mutations in the zebrafish KMT2A gene and study whether either the KMT2A-MLLT3 or KMT2A-MLLT1 fusion impacts blood development and speeds up development of leukemia. The researchers will carry out drug screens targeting key disease pathways to identify potential new effective and safe treatments for this vulnerable group of patients.
Dr. Mick Bhatia
McMaster University, Hamilton
Improving understanding of epigenetically regulated genes in MDS to AML evolution
Myelodysplastic syndromes (MDS) are a type of blood disorder with poor outcomes due to an increased susceptibility to infection and failure of blood production. Most importantly, one of every three MDS patients progresses into a lethal secondary disease called acute myeloid leukemia (AML). Today, there is no way to predict when MDS will worsen to AML and no clinical measures are available to detect or prevent it. This is mainly due to our lack of understanding of the disease process at the cellular level.
Previously, the use of a type of drug called “hypomethylating agents” showed encouraging but temporary effects in MDS and AML. However, these drugs have lots of non-specific effects and affect the expression of hundreds of genes at once that have unknown roles in disease or side effects.
Identifying specific areas of DNA that regulate a smaller and specific set of genes involved in MDS disease and evolution to AML would provide the knowledge needed to create specific drugs with long-lasting effects and fewer side effects like has been done for other cancers. The goal of this study is to identify the DNA regions and genes they control as new and very specific targets for development of entirely new therapeutics for MDS and AML.
Myelodysplastic syndromes (MDS) are a type of blood disorder with poor outcomes due to an increased susceptibility to infection and failure of blood production. Most importantly, one of every three MDS patients progresses into a lethal secondary disease called acute myeloid leukemia (AML). Today, there is no way to predict when MDS will worsen to AML and no clinical measures are available to detect or prevent it. This is mainly due to our lack of understanding of the disease process at the cellular level.
Previously, the use of a type of drug called “hypomethylating agents” showed encouraging but temporary effects in MDS and AML. However, these drugs have lots of non-specific effects and affect the expression of hundreds of genes at once that have unknown roles in disease or side effects.
Identifying specific areas of DNA that regulate a smaller and specific set of genes involved in MDS disease and evolution to AML would provide the knowledge needed to create specific drugs with long-lasting effects and fewer side effects like has been done for other cancers. The goal of this study is to identify the DNA regions and genes they control as new and very specific targets for development of entirely new therapeutics for MDS and AML.
Dr. Steven Chan
University Health Network, Toronto
Role of TPO receptor signaling in TET2 mutation-driven clonal hematopoiesis
Clonal Hematopoiesis of Indeterminate Potential (CHIP) refers to the presence of blood cells carrying mutations associated with leukemia in individuals without evidence of a blood disorder. Individuals with CHIP are at a substantially higher risk of developing blood cancers, including acute leukemia, than those without CHIP. The time from having CHIP identified to a diagnosis of blood cancer can be many years. This finding opens the intriguing possibility of interventions to prevent blood cancers. To achieve this goal, we need to first understand how normal and mutated blood cells behave differently. This knowledge will allow us to design effective and safe interventions.
One of the most common mutations in CHIP is in a gene called TET2. Dr. Chan’s research team recently discovered that blood cells with mutations in TET2 are more dependent on a hormone called thrombopoietin to grow and survive than are normal blood cells. This finding suggests that if thrombopoietin can be blocked, it may be possible to selectively destroy the mutated blood cells. Because these studies were done using artificial cells, the finding must be confirmed using human cells. In this project, the researchers will study if human blood cells with the TET2 mutation are also more dependent on thrombopoietin. If successful, the finding will help establish a potential approach for eliminating CHIP and, eventually, preventing blood cancers.
UFCW Special Recognition Award Recipient 2022
Clonal Hematopoiesis of Indeterminate Potential (CHIP) refers to the presence of blood cells carrying mutations associated with leukemia in individuals without evidence of a blood disorder. Individuals with CHIP are at a substantially higher risk of developing blood cancers, including acute leukemia, than those without CHIP. The time from having CHIP identified to a diagnosis of blood cancer can be many years. This finding opens the intriguing possibility of interventions to prevent blood cancers. To achieve this goal, we need to first understand how normal and mutated blood cells behave differently. This knowledge will allow us to design effective and safe interventions.
One of the most common mutations in CHIP is in a gene called TET2. Dr. Chan’s research team recently discovered that blood cells with mutations in TET2 are more dependent on a hormone called thrombopoietin to grow and survive than are normal blood cells. This finding suggests that if thrombopoietin can be blocked, it may be possible to selectively destroy the mutated blood cells. Because these studies were done using artificial cells, the finding must be confirmed using human cells. In this project, the researchers will study if human blood cells with the TET2 mutation are also more dependent on thrombopoietin. If successful, the finding will help establish a potential approach for eliminating CHIP and, eventually, preventing blood cancers.
UFCW Special Recognition Award Recipient 2022
Dr. Connie Eaves
BC Cancer, Vancouver
In vivo xenograft modeling of human AML subclone responses to therapy
The long-term goal of this project is to develop a new model system that will have wide applicability to predict the response of AML to new therapies. This project will focus on a model that will simulate the widespread problem of the reappearance of resistant and usually lethal disease after an initial response to treatment. The immediate objective is to develop a system that mimics therapy-resistant AML cells after being exposed to a standard partially effective treatment.
In this first series of studies, the researchers will use a powerful new approach to characterize the subtypes of AML cells in samples and compare the results to what was seen in the lab, before and after exposure to the treatment.
The results will establish the feasibility of using this approach for future use of this model to identify treatments that prevent subsequent relapses from resistant, as opposed to incomplete elimination, of treatment-sensitive cells. This will then set the stage for creating new ways to anticipate, characterize and design improved methods to eliminate anticipated resistant AML cell types.
The long-term goal of this project is to develop a new model system that will have wide applicability to predict the response of AML to new therapies. This project will focus on a model that will simulate the widespread problem of the reappearance of resistant and usually lethal disease after an initial response to treatment. The immediate objective is to develop a system that mimics therapy-resistant AML cells after being exposed to a standard partially effective treatment.
In this first series of studies, the researchers will use a powerful new approach to characterize the subtypes of AML cells in samples and compare the results to what was seen in the lab, before and after exposure to the treatment.
The results will establish the feasibility of using this approach for future use of this model to identify treatments that prevent subsequent relapses from resistant, as opposed to incomplete elimination, of treatment-sensitive cells. This will then set the stage for creating new ways to anticipate, characterize and design improved methods to eliminate anticipated resistant AML cell types.
Dr. Kolja Eppert
McGill University, Montreal
New therapeutics targeting leukemia stem cells
The goal of this project is to identify drugs that can target the rare cells that cause treatment failure in leukemia, specifically leukemic stem cells (LSCs). AML is sustained by LSCs that act somewhat like normal stem cells in that they are the ‘root’ of the cancer and need to be eliminated to achieve a cure.
Therapy for childhood and adult acute myeloid leukemia (AML) involves extremely intense and toxic treatments. This can impair the development of children and can cause long-term cardiac dysfunction, affect fertility and cause secondary cancers later in life. Even with this aggressive treatment, the majority of these patients do not respond to therapy, or the leukemia returns later. New treatments are desperately needed to improve the outcome and reduce toxicity.
The researchers have identified 15 compounds that can selectively eliminate LSCs. They will confirm the effectiveness of the best of these compounds against LSCs in a larger set of AML samples and test toxicity. This will allow for the selection of the best compounds for further study and development.
The goal of this project is to identify drugs that can target the rare cells that cause treatment failure in leukemia, specifically leukemic stem cells (LSCs). AML is sustained by LSCs that act somewhat like normal stem cells in that they are the ‘root’ of the cancer and need to be eliminated to achieve a cure.
Therapy for childhood and adult acute myeloid leukemia (AML) involves extremely intense and toxic treatments. This can impair the development of children and can cause long-term cardiac dysfunction, affect fertility and cause secondary cancers later in life. Even with this aggressive treatment, the majority of these patients do not respond to therapy, or the leukemia returns later. New treatments are desperately needed to improve the outcome and reduce toxicity.
The researchers have identified 15 compounds that can selectively eliminate LSCs. They will confirm the effectiveness of the best of these compounds against LSCs in a larger set of AML samples and test toxicity. This will allow for the selection of the best compounds for further study and development.
Dr. Trang Hoang
Université de Montréal
Uncovering tumor specific antigens in T-cell acute lymphoblastic leukemia
Standard of care in pediatric T-cell acute lymphoblastic leukemia (T-ALL) includes topoisomerase inhibitors, microtubule targeting drugs and corticosteroids that are administered over a two-year treatment regimen. Despite cure rates of 90%, the long duration of such drastic chemotherapy in pediatric patients has immediate as well as long-term consequences that irreversibly alter their quality of life. Moreover, prognosis is very poor in adolescent/adult T-ALL, as well as in relapse T-ALL at all ages. Treatment resistant disease suggests that current chemotherapy fails to target leukemic cell vulnerabilities.
In this era of precision medicine, the study aims to identify tumor specific antigens that can be used to trigger an immune reaction against these TSAs, which are absent in normal T cells and other normal cell types. The proposed work will pave the way to precision medicine at its best, based on the unique capacity of the immune system to mount a highly specific immune response against antigens that are detectable in leukemic cells only, sparing normal cells.
Standard of care in pediatric T-cell acute lymphoblastic leukemia (T-ALL) includes topoisomerase inhibitors, microtubule targeting drugs and corticosteroids that are administered over a two-year treatment regimen. Despite cure rates of 90%, the long duration of such drastic chemotherapy in pediatric patients has immediate as well as long-term consequences that irreversibly alter their quality of life. Moreover, prognosis is very poor in adolescent/adult T-ALL, as well as in relapse T-ALL at all ages. Treatment resistant disease suggests that current chemotherapy fails to target leukemic cell vulnerabilities.
In this era of precision medicine, the study aims to identify tumor specific antigens that can be used to trigger an immune reaction against these TSAs, which are absent in normal T cells and other normal cell types. The proposed work will pave the way to precision medicine at its best, based on the unique capacity of the immune system to mount a highly specific immune response against antigens that are detectable in leukemic cells only, sparing normal cells.
Dr. Francois Mercier
Sir Mortimer B. Davis-Jewish General Hospital, Montreal
Targeting the metabolic plasticity of acute myeloid leukemia through inhibition of eIF4A
Acute myeloid leukemia (AML) is an aggressive cancer of the blood and its treatment remains challenging. High doses of chemotherapy, often accompanied by stem cell transplantation, can lead to a cure, but many patients are not eligible for this treatment due to advanced age or other health conditions.
The knowledge of the specific DNA alterations within AML cells has led to the development of specific inhibitors of altered proteins, leading to promising responses, especially for those with other medical conditions or relapsed disease. However, these responses usually don’t last long and, invariably, treatment resistance occurs.
Preliminary data from the research team suggests that, in AML cells, resistance to therapy occurs through the activation of a specific factor called eukaryotic initiation factor 4A (eIF4A), which promotes the expression of several pro-survival proteins. Furthermore, they found that treatment with an inhibitor of eIF4A decreases AML burden and enhances the effect of other known therapies.
Using these findings, in this project the researchers will characterize the mechanism of action of eIF4A inhibition and test the efficacy of new therapeutic combinations with eIF4A inhibitors. Their aim is to identify a new way of treating AML that could enhance current therapies and prevent resistance to treatment.
Acute myeloid leukemia (AML) is an aggressive cancer of the blood and its treatment remains challenging. High doses of chemotherapy, often accompanied by stem cell transplantation, can lead to a cure, but many patients are not eligible for this treatment due to advanced age or other health conditions.
The knowledge of the specific DNA alterations within AML cells has led to the development of specific inhibitors of altered proteins, leading to promising responses, especially for those with other medical conditions or relapsed disease. However, these responses usually don’t last long and, invariably, treatment resistance occurs.
Preliminary data from the research team suggests that, in AML cells, resistance to therapy occurs through the activation of a specific factor called eukaryotic initiation factor 4A (eIF4A), which promotes the expression of several pro-survival proteins. Furthermore, they found that treatment with an inhibitor of eIF4A decreases AML burden and enhances the effect of other known therapies.
Using these findings, in this project the researchers will characterize the mechanism of action of eIF4A inhibition and test the efficacy of new therapeutic combinations with eIF4A inhibitors. Their aim is to identify a new way of treating AML that could enhance current therapies and prevent resistance to treatment.
Dr. Anastasia Nijnik
McGill University, Montreal
MYSM1 as a drug target for B-cell lymphoma: Impact on anti-tumour immunity
The protein cMYC is a major regulator of gene expression and the genetic changes leading to cMYC hyperactivation occur in many cancers, including lymphomas. Such lymphomas remain difficult to treat and result in a poor disease prognosis.
In a previous study funded by the LLSC, the researchers demonstrated the cooperation of cMYC with another protein and enzyme called MYSM1 that regulates gene expression in cancer cells. Furthermore, they established that the loss of MYSM1 can delay lymphoma progression when cMYC is hyperactivated. This finding serves as a strong proof-of-concept for targeting MYSM1 in cancer cells as a novel therapy for cMYC driven lymphoma.
Immunotherapy is revolutionizing cancer treatment in the clinic. Importantly, MYSM1 is an important regulator of gene expression not only in cancer cells but also in immune cells. However, its role in anti-tumour immunity remains unknown. In this current study, the researchers will assess the effects of targeting MYSM1 on the immune cell functions and anti-tumor immunity in cMYC lymphoma models. This represents the essential next step for further translational development of their research – to establish MYSM1 as a drug target for cMYC driven lymphoma.
The protein cMYC is a major regulator of gene expression and the genetic changes leading to cMYC hyperactivation occur in many cancers, including lymphomas. Such lymphomas remain difficult to treat and result in a poor disease prognosis.
In a previous study funded by the LLSC, the researchers demonstrated the cooperation of cMYC with another protein and enzyme called MYSM1 that regulates gene expression in cancer cells. Furthermore, they established that the loss of MYSM1 can delay lymphoma progression when cMYC is hyperactivated. This finding serves as a strong proof-of-concept for targeting MYSM1 in cancer cells as a novel therapy for cMYC driven lymphoma.
Immunotherapy is revolutionizing cancer treatment in the clinic. Importantly, MYSM1 is an important regulator of gene expression not only in cancer cells but also in immune cells. However, its role in anti-tumour immunity remains unknown. In this current study, the researchers will assess the effects of targeting MYSM1 on the immune cell functions and anti-tumor immunity in cMYC lymphoma models. This represents the essential next step for further translational development of their research – to establish MYSM1 as a drug target for cMYC driven lymphoma.
Dr. Christopher Paige
University Health Network, Toronto
Cytokine induced immune responses to AML: A Phase 1 trial
Dr. Paige and his research team began to treat leukemia with a novel form of immunotherapy prior to the onset of COVID-19. In this form of immunotherapy, leukemia cells were obtained from a patient and engineered to secrete a molecule called interleukin 12 (IL-12). IL-12 is a powerful immune stimulator that, in fact, is too strong to simply directly inject. There is, therefore, a worldwide effort to find less toxic ways to introduce IL-12 to the site where a leukemia cell meets the cells of the immune system.
The team has had great success, in experimental systems, in enabling the leukemia cell to do this itself. This is accomplished by treating the leukemia cells with a viral vector that introduces the gene for IL-12. These modified leukemia cells are then returned to the same patient where they appear to initiate an anti-leukemia immune response. Once activated, the immune system cells no longer require IL-12 and are free to kill other leukemia cells. To date the researchers have treated six participants in an early phase (phase 1) clinical trial designed to test the safety of this approach. They plan to treat six additional participants to complete this trial.
Dr. Paige and his research team began to treat leukemia with a novel form of immunotherapy prior to the onset of COVID-19. In this form of immunotherapy, leukemia cells were obtained from a patient and engineered to secrete a molecule called interleukin 12 (IL-12). IL-12 is a powerful immune stimulator that, in fact, is too strong to simply directly inject. There is, therefore, a worldwide effort to find less toxic ways to introduce IL-12 to the site where a leukemia cell meets the cells of the immune system.
The team has had great success, in experimental systems, in enabling the leukemia cell to do this itself. This is accomplished by treating the leukemia cells with a viral vector that introduces the gene for IL-12. These modified leukemia cells are then returned to the same patient where they appear to initiate an anti-leukemia immune response. Once activated, the immune system cells no longer require IL-12 and are free to kill other leukemia cells. To date the researchers have treated six participants in an early phase (phase 1) clinical trial designed to test the safety of this approach. They plan to treat six additional participants to complete this trial.
Dr. David Spaner
Sunnybrook Research Institute, Toronto
IL10 in the treatment of chronic leukemia
Ibrutinib is one of a class of drugs called BTK inhibitors that form an important new treatment for blood cancer. Unfortunately, these drugs are unable to cure the disease on their own. Dr. Spaner’s group has found that a protein called IL10 kills blood cancer cells when ibrutinib is present. However, ibrutinib decreases IL10 levels, which may be an Achilles heel for BTK inhibitors.
In this project, Dr. Spaner will examine the ways that IL10 affects blood cancer cells in the presence of ibrutinib. He will also determine if infusing IL10 together with ibrutinib can be a safe and more effective way to treat blood cancers. Cancer cells from patients with chronic lymphocytic leukemia (CLL) will be studied in this project.
The results of this project are expected to support using ibrutinib and IL10 to treat CLL. This approach is expected to increase cure rates in CLL and many other forms of cancer.
Ibrutinib is one of a class of drugs called BTK inhibitors that form an important new treatment for blood cancer. Unfortunately, these drugs are unable to cure the disease on their own. Dr. Spaner’s group has found that a protein called IL10 kills blood cancer cells when ibrutinib is present. However, ibrutinib decreases IL10 levels, which may be an Achilles heel for BTK inhibitors.
In this project, Dr. Spaner will examine the ways that IL10 affects blood cancer cells in the presence of ibrutinib. He will also determine if infusing IL10 together with ibrutinib can be a safe and more effective way to treat blood cancers. Cancer cells from patients with chronic lymphocytic leukemia (CLL) will be studied in this project.
The results of this project are expected to support using ibrutinib and IL10 to treat CLL. This approach is expected to increase cure rates in CLL and many other forms of cancer.
Dr. Andrew Weng
BC Cancer, Vancouver
Functional modeling of MYC translocation in follicular lymphoma
Follicular lymphoma is a slow growing but incurable cancer of the lymph nodes. It can spontaneously transform to a more aggressive form of lymphoma requiring chemotherapy. Mutations in certain genes occur frequently in follicular lymphoma, but how these mutated genes interfere with normal cell function remains poorly understood.
To study how these mutated genes operate in human cells, the research group will introduce them into normal lymph node cells that have been obtained from biopsy cells. The researchers will test the effects of the mutated genes in these biopsy cells using a new kind of assay (an investigative procedure) where cells are grown in the lab as miniature organs, or “organoids”, that more accurately recreate the conditions of a lymph node in the human body.
The team will test a new idea that specific gene mutations alter the cell’s DNA in a manner that results in the faulty repair of naturally occurring breaks in the DNA strands, leading to uncontrolled expression of mutated genes. By understanding exactly how these genes change the cell’s DNA, the researchers will be able to correct the problem and allow the cell’s normal repair mechanisms to function properly again. The results from this work can be more directly translated to new therapies because they have been tested in cells that have come directly from patients.
Follicular lymphoma is a slow growing but incurable cancer of the lymph nodes. It can spontaneously transform to a more aggressive form of lymphoma requiring chemotherapy. Mutations in certain genes occur frequently in follicular lymphoma, but how these mutated genes interfere with normal cell function remains poorly understood.
To study how these mutated genes operate in human cells, the research group will introduce them into normal lymph node cells that have been obtained from biopsy cells. The researchers will test the effects of the mutated genes in these biopsy cells using a new kind of assay (an investigative procedure) where cells are grown in the lab as miniature organs, or “organoids”, that more accurately recreate the conditions of a lymph node in the human body.
The team will test a new idea that specific gene mutations alter the cell’s DNA in a manner that results in the faulty repair of naturally occurring breaks in the DNA strands, leading to uncontrolled expression of mutated genes. By understanding exactly how these genes change the cell’s DNA, the researchers will be able to correct the problem and allow the cell’s normal repair mechanisms to function properly again. The results from this work can be more directly translated to new therapies because they have been tested in cells that have come directly from patients.
Dr. Yuliang Wu
The University of Saskatchewan
DDX41 as a new therapeutic target in MDS and AML
Myelodysplastic syndromes (MDS) are a group of blood cancers of the blood and bone marrow. With MDS, the bone marrow does not produce enough healthy blood cells. About 30% of MDS cases progress to acute myeloid leukemia (AML).
The mainstays of MDS/AML treatment are chemotherapy with azacytidine and cytarabine, which have been in use for more than 40 years. However, the survival rate is low, so there is a pressing need to develop better therapies.
Mutations in the DDX41 gene are associated with MDS and AML and the mutation R525H is the most frequently identified mutation in patients. Recently, the research group found that the DDX41-R525H protein affects cell function in a way that that causes excessive innate immune activation, which has implications in cancer initiation and progression. This has led the research team to study the development of specific inhibitors for R525H protein.
The researchers will attempt to identify new molecules that selectively kill leukemia cells by targeting DDX41. The findings could result in potent drug target DDX41 for MDS and AML treatment.
Myelodysplastic syndromes (MDS) are a group of blood cancers of the blood and bone marrow. With MDS, the bone marrow does not produce enough healthy blood cells. About 30% of MDS cases progress to acute myeloid leukemia (AML).
The mainstays of MDS/AML treatment are chemotherapy with azacytidine and cytarabine, which have been in use for more than 40 years. However, the survival rate is low, so there is a pressing need to develop better therapies.
Mutations in the DDX41 gene are associated with MDS and AML and the mutation R525H is the most frequently identified mutation in patients. Recently, the research group found that the DDX41-R525H protein affects cell function in a way that that causes excessive innate immune activation, which has implications in cancer initiation and progression. This has led the research team to study the development of specific inhibitors for R525H protein.
The researchers will attempt to identify new molecules that selectively kill leukemia cells by targeting DDX41. The findings could result in potent drug target DDX41 for MDS and AML treatment.
Blood Cancer Quality of Life Grants
Quality of life issues for blood cancer patients have been less well studied than other areas of care. There are many medical and non-medical consequences of treatments that vary with age, sex, gender, ethnicity, type of blood cancer and treatment.
The intent of this funding opportunity is to support new research designed to address quality of life challenges experienced by Canadians affected by blood cancers. Quality of life cancer research has the potential to make a significant impact on the burden of disease in patients, survivors and caregivers.
Dr. Sarit Assouline
Jewish General Hospital, Montreal
Using artificial intelligence and a serious illness conversations guide to improve the quality of life and establish end-of-life markers.
It can be hard for hematologists to predict when their patient is close to death. This may mean that discussions about end-of-life (EOL) care can happen too late, which can impact the quality of care.
To better support these individuals and their families facing this circumstance, the researchers will test an artificial intelligence (AI) tool that has been shown to predict when individuals with a general cancer are at highest risk of death. In this study, the AI tool will be used with those experiencing a blood cancer to identify those who are at highest risk. The healthcare team will then use a serious illness conversations guide to support discussions about EOL care and patients will be interviewed to determine how support can be improved.
Ultimately, the timely identification of those at high-risk, use of the guide, and refining of quality of life-EOL markers through feedback will allow the healthcare team to work with patients and their families to structure an EOL approach to suit the needs.
Funded in partnership with the Canadian Cancer Society
It can be hard for hematologists to predict when their patient is close to death. This may mean that discussions about end-of-life (EOL) care can happen too late, which can impact the quality of care.
To better support these individuals and their families facing this circumstance, the researchers will test an artificial intelligence (AI) tool that has been shown to predict when individuals with a general cancer are at highest risk of death. In this study, the AI tool will be used with those experiencing a blood cancer to identify those who are at highest risk. The healthcare team will then use a serious illness conversations guide to support discussions about EOL care and patients will be interviewed to determine how support can be improved.
Ultimately, the timely identification of those at high-risk, use of the guide, and refining of quality of life-EOL markers through feedback will allow the healthcare team to work with patients and their families to structure an EOL approach to suit the needs.
Funded in partnership with the Canadian Cancer Society
Dr. Karine Bilodeau and Dr. Caroline Arbour
Université de Montréal
ImPROve quality of life after blood cancer: Predict and act on SLEEP
Sleep disruptions and unrelenting fatigue are commonly reported after the end of treatment for a blood cancer. In addition to its immediate impact on an individual’s daytime activity, poor sleep could also affect their quality of life. The PROSLEEP study will provide the first thorough exploration of sleep in recently treated blood cancer patients and its connection to fatigue and quality of life. In this study, the research team will monitor the rest and activity cycle of study participants. Those individuals with unresolved sleep problems will be offered tools and strategies to help improve their sleep. The results of the study will be used to further refine these tools and strategies in preparation for a future randomized controlled clinical trial.
Funded in partnership with the Canadian Cancer Society
Sleep disruptions and unrelenting fatigue are commonly reported after the end of treatment for a blood cancer. In addition to its immediate impact on an individual’s daytime activity, poor sleep could also affect their quality of life. The PROSLEEP study will provide the first thorough exploration of sleep in recently treated blood cancer patients and its connection to fatigue and quality of life. In this study, the research team will monitor the rest and activity cycle of study participants. Those individuals with unresolved sleep problems will be offered tools and strategies to help improve their sleep. The results of the study will be used to further refine these tools and strategies in preparation for a future randomized controlled clinical trial.
Funded in partnership with the Canadian Cancer Society
Dr. Samantha Mayo
University Health Network, Toronto
Impact of treatment on quality of life for relapsed and refractory B-cell lymphoma
Lymphoma patients who experience relapse after treatment or do not get into remission (refractory) respond poorly to standard chemotherapy. While autologous stem cell transplant (ASCT) has traditionally been the treatment of choice, chimeric antigen receptor T-cell (CAR T) therapy has emerged as a new standard of care for relapsed or refractory (RR) B-cell lymphoma.
This study aims to understand the survival benefits and the impact of these treatments on quality of life which may inform decisions regarding treatment and supportive services. The researchers will evaluate quality of life outcomes among adults who were treated for RR B-cell lymphoma with either ASCT or CAR T using feedback from the individuals who have received these treatments. The analysis of the results will generate a new understanding about the long-term quality of life outcomes among this population, which will help in the development of interventions for early identification those at high-risk and supportive care measures.
Funded in partnership with the Canadian Cancer Society
Lymphoma patients who experience relapse after treatment or do not get into remission (refractory) respond poorly to standard chemotherapy. While autologous stem cell transplant (ASCT) has traditionally been the treatment of choice, chimeric antigen receptor T-cell (CAR T) therapy has emerged as a new standard of care for relapsed or refractory (RR) B-cell lymphoma.
This study aims to understand the survival benefits and the impact of these treatments on quality of life which may inform decisions regarding treatment and supportive services. The researchers will evaluate quality of life outcomes among adults who were treated for RR B-cell lymphoma with either ASCT or CAR T using feedback from the individuals who have received these treatments. The analysis of the results will generate a new understanding about the long-term quality of life outcomes among this population, which will help in the development of interventions for early identification those at high-risk and supportive care measures.
Funded in partnership with the Canadian Cancer Society
Dr. Hira Mian
McMaster University, Hamilton
Developing a dynamic predictive method to improve quality of life for patients with incurable blood cancer
Multiple myeloma and indolent (slow growing and slow spreading) non-Hodgkin lymphoma are incurable blood cancers. Individuals with these cancers suffer from many symptoms and a poor quality of life at multiple time points during their cancer experience.
The researchers will use a dynamic model to predict outcomes at different points in time during a cancer experience. This model will be developed with the input of patients, caregivers, and healthcare providers. The goal of the study is to provide information that will help guide meaningful discussions and help plan for future cancer needs and to, ultimately, improve future quality of life for this group.
The study will test a new way to predict how these cancers will progress, including:
• Survival
• Ability to perform tasks required for independent living
• Moderate to severe symptoms of pain
• Depression
• Overall well being
Multiple myeloma and indolent (slow growing and slow spreading) non-Hodgkin lymphoma are incurable blood cancers. Individuals with these cancers suffer from many symptoms and a poor quality of life at multiple time points during their cancer experience.
The researchers will use a dynamic model to predict outcomes at different points in time during a cancer experience. This model will be developed with the input of patients, caregivers, and healthcare providers. The goal of the study is to provide information that will help guide meaningful discussions and help plan for future cancer needs and to, ultimately, improve future quality of life for this group.
The study will test a new way to predict how these cancers will progress, including:
• Survival
• Ability to perform tasks required for independent living
• Moderate to severe symptoms of pain
• Depression
• Overall well being
Dr. Edith Pituskin
University of Alberta, Edmonton
APOLLO: Personalized rehAbilitation PrOgram in aLLOgeneic bone marrow transplantation
People who require an allogeneic stem cell transplant (cells from a donor) for leukemia and lymphoma have to undergo very aggressive treatment prior to their transplant.
As a result, they have devastating physical and psychological side effects during and for years after the procedure. The situation is worsened by the fact that many receiving this type of treatment live several hours away from treatment and transplant centres, leaving them on their own to manage debilitating side effects.
In this qualitative study, Dr. Pituskin and her team aim to learn about the experiences of people undergoing an allogeneic transplant when they receive access to a supportive care app and telephone support from nursing, exercise and nutrition experts. The aim is to determine the most helpful type and best timing of supportive care from those who have first-hand knowledge.
Funded in partnership with the Canadian Cancer Society
People who require an allogeneic stem cell transplant (cells from a donor) for leukemia and lymphoma have to undergo very aggressive treatment prior to their transplant.
As a result, they have devastating physical and psychological side effects during and for years after the procedure. The situation is worsened by the fact that many receiving this type of treatment live several hours away from treatment and transplant centres, leaving them on their own to manage debilitating side effects.
In this qualitative study, Dr. Pituskin and her team aim to learn about the experiences of people undergoing an allogeneic transplant when they receive access to a supportive care app and telephone support from nursing, exercise and nutrition experts. The aim is to determine the most helpful type and best timing of supportive care from those who have first-hand knowledge.
Funded in partnership with the Canadian Cancer Society
Dr. Robin Urquhart
Dalhousie University, Halifax
Defining the successful transition of care for adolescent and young adult blood cancer survivors
Survivors of childhood, adolescent and young adult blood cancers are at high risk for a variety of health problems long after their treatment ends. As such, they must be monitored for a long time to detect and care for health problems that may develop.
To ensure that they are receiving the most effective care, these young survivors face transition to one or more healthcare providers. Currently, this transition of care is not well researched and there is no clear definition of what constitutes the successful transfer of care. For this project, a team of patient partners, physicians and researchers will work together to help define what represents the successful transition of care among young blood cancer survivors. The results of this work will be used to improve not only their care, but also the outcomes of their care (e.g., quality of life).
Survivors of childhood, adolescent and young adult blood cancers are at high risk for a variety of health problems long after their treatment ends. As such, they must be monitored for a long time to detect and care for health problems that may develop.
To ensure that they are receiving the most effective care, these young survivors face transition to one or more healthcare providers. Currently, this transition of care is not well researched and there is no clear definition of what constitutes the successful transfer of care. For this project, a team of patient partners, physicians and researchers will work together to help define what represents the successful transition of care among young blood cancer survivors. The results of this work will be used to improve not only their care, but also the outcomes of their care (e.g., quality of life).
Pediatric Blood Cancer Research Innovation Grants
In the current era of targeted and immuno-oncology drugs being developed for adults, very few successful examples have been translated to childhood blood cancer treatment.
Clear advances have occurred, but cure rates remain low for certain blood cancer types, along with considerable long-term effects from traditional therapies.
These projects will challenge the current pediatric blood cancer landscape and address unmet needs for pediatric blood cancers.
Dr. Jayne Danska
SickKids, Toronto
Targeting pediatric central nervous system leukemia
Survival for children with B-cell acute lymphoblastic leukemia (B-ALL), the most common cancer of childhood, is now greater than 85%. However, treatment of ALL in the central nervous system (CNS; brain and spine) remains a major challenge. It is understood that ALL cells can invade the CNS. In fact, introduction of preventative CNS irradiation and injection of chemotherapy drugs into the fluid surrounding brain and spine provided the first breakthrough in the development of a successful leukemia treatment.
The challenge now is to solve two main problems:
• Understanding how ALL cells gain access to the CNS and which children are at highest risk
• Developing better treatments to block CNS invasion that are less harmful to the development of children’s brains
The research team has discovered two new routes of ALL entry into the CNS. Most importantly, they have demonstrated that potential new drugs that can block these entryways have worked. They now will work to gain a better understanding of how ALL cells invade the CN and develop a better test to predict which children are at greater risk for this problem. The results of the research will support future clinical trials of new drugs that prevent and treat CNS relapse more effectively and provide better quality of life for survivors.
Survival for children with B-cell acute lymphoblastic leukemia (B-ALL), the most common cancer of childhood, is now greater than 85%. However, treatment of ALL in the central nervous system (CNS; brain and spine) remains a major challenge. It is understood that ALL cells can invade the CNS. In fact, introduction of preventative CNS irradiation and injection of chemotherapy drugs into the fluid surrounding brain and spine provided the first breakthrough in the development of a successful leukemia treatment.
The challenge now is to solve two main problems:
• Understanding how ALL cells gain access to the CNS and which children are at highest risk
• Developing better treatments to block CNS invasion that are less harmful to the development of children’s brains
The research team has discovered two new routes of ALL entry into the CNS. Most importantly, they have demonstrated that potential new drugs that can block these entryways have worked. They now will work to gain a better understanding of how ALL cells invade the CN and develop a better test to predict which children are at greater risk for this problem. The results of the research will support future clinical trials of new drugs that prevent and treat CNS relapse more effectively and provide better quality of life for survivors.
Dr. John Dick and Dr. Eric Lechman
University Health Network, Toronto
Investigating ciliopathy as a predisposition for childhood leukemia
Childhood leukemia is a challenging setting to explain the origins of leukemia, since the first genetic alterations occur during pregnancy.
Down syndrome (DS) is caused by the presence of an extra chromosome 21 (trisomy 21-T21) and DS children have a 150-fold increased risk of developing a pre-leukemia syndrome that often evolves to leukemia. The research team’s recent landmark DS study demonstrated that DS pre-leukemia arises only from rare hematopoietic (blood) stem cells (HSC). What remains unclear is how T21 can lead to HSCs becoming cancerous.
Dr. Dick and his team propose that malfunctioning cilia (hair like structures found on the cell surface)
may play an unappreciated role in DS blood cells and DS abnormal hematopoiesis (formation of blood cells). However, hematological function or malignancy have not been previously linked to cilia defects.
As a first step, the researchers will examine ~120,000 single blood progenitor (immature) cells with state-of-the-art DNA structure, RNA and protein analyses to reveal differences between DS and normal human blood cells. The aim of the study is to provide insight into the influence of trisomy 21 on leukemia development.
Childhood leukemia is a challenging setting to explain the origins of leukemia, since the first genetic alterations occur during pregnancy.
Down syndrome (DS) is caused by the presence of an extra chromosome 21 (trisomy 21-T21) and DS children have a 150-fold increased risk of developing a pre-leukemia syndrome that often evolves to leukemia. The research team’s recent landmark DS study demonstrated that DS pre-leukemia arises only from rare hematopoietic (blood) stem cells (HSC). What remains unclear is how T21 can lead to HSCs becoming cancerous.
Dr. Dick and his team propose that malfunctioning cilia (hair like structures found on the cell surface)
may play an unappreciated role in DS blood cells and DS abnormal hematopoiesis (formation of blood cells). However, hematological function or malignancy have not been previously linked to cilia defects.
As a first step, the researchers will examine ~120,000 single blood progenitor (immature) cells with state-of-the-art DNA structure, RNA and protein analyses to reveal differences between DS and normal human blood cells. The aim of the study is to provide insight into the influence of trisomy 21 on leukemia development.
Dr. Cynthia Guidos
SickKids, Toronto
Identifying the genetic changes that lead to ruxolitinib resistance
Modern chemotherapy regimens can cure acute lymphoblastic leukemia (ALL) in most children, adolescents, and young adults. Unfortunately, outcomes remain poor for children whose ALL is caused by certain high-risk genetic mutations, known as Ph-like ALL. This subtype occurs very commonly in children and is more frequent in individuals of Hispanic/Latino and Indigenous ancestry. Ph-like ALL often comes back even with the best available chemotherapy.
A new targeted therapy called ruxolitinib was created to block an important pathway that contributes to the cancerous behaviour of Ph-like ALL cells. A phase 2 clinical trial is ongoing to test whether adding ruxolitinib to chemotherapy can decrease relapses in children with Ph-like ALL. However, some children have already relapsed, suggesting that their leukemia cells found a way to outsmart the drugs and become resistant.
In this project, the researchers are studying blood and bone marrow samples from pediatric Ph-like ALL participants in the clinical trial. They hope to learn why leukemia cells can sometimes outsmart the drugs and lead to relapse, either by developing DNA mutations or rewiring the pathways inside the cells to hide from the drugs. The results will be used to identify new therapies that attack other leukemia cell targets with a goal of overcoming or even preventing resistance to ruxolitinib in patients with Ph-like ALL.
Funded in partnership with Kindred Foundation
Modern chemotherapy regimens can cure acute lymphoblastic leukemia (ALL) in most children, adolescents, and young adults. Unfortunately, outcomes remain poor for children whose ALL is caused by certain high-risk genetic mutations, known as Ph-like ALL. This subtype occurs very commonly in children and is more frequent in individuals of Hispanic/Latino and Indigenous ancestry. Ph-like ALL often comes back even with the best available chemotherapy.
A new targeted therapy called ruxolitinib was created to block an important pathway that contributes to the cancerous behaviour of Ph-like ALL cells. A phase 2 clinical trial is ongoing to test whether adding ruxolitinib to chemotherapy can decrease relapses in children with Ph-like ALL. However, some children have already relapsed, suggesting that their leukemia cells found a way to outsmart the drugs and become resistant.
In this project, the researchers are studying blood and bone marrow samples from pediatric Ph-like ALL participants in the clinical trial. They hope to learn why leukemia cells can sometimes outsmart the drugs and lead to relapse, either by developing DNA mutations or rewiring the pathways inside the cells to hide from the drugs. The results will be used to identify new therapies that attack other leukemia cell targets with a goal of overcoming or even preventing resistance to ruxolitinib in patients with Ph-like ALL.
Funded in partnership with Kindred Foundation
Dr. Maja Krajinovic
Centre Hospitalier Universitaire Sainte-Justine, Montreal
Genetic-based treatment adaptation for childhood ALL
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Modern treatments have led to a remarkable improvement of cure rates, shifting the focus of the research toward decreasing the toxicity burden of chemotherapy. Intensive anti-cancer treatment leads to serious adverse drug reactions (ADRs) and even to long-term side effects. Genetic factors may influence the child’s risk of developing treatment-related toxicities.
This project will analyse the genetics of ADRs in childhood ALL. The researchers have identified genetic variations through previous studies, but they do not yet know if these genetic variations can help predict ADRs and how they can be used to better adjust treatment. This study addresses these questions and will provide important insight of how a person’s genetics can affect the response to certain drugs, leading to better treatment of childhood ALL patients.
Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Modern treatments have led to a remarkable improvement of cure rates, shifting the focus of the research toward decreasing the toxicity burden of chemotherapy. Intensive anti-cancer treatment leads to serious adverse drug reactions (ADRs) and even to long-term side effects. Genetic factors may influence the child’s risk of developing treatment-related toxicities.
This project will analyse the genetics of ADRs in childhood ALL. The researchers have identified genetic variations through previous studies, but they do not yet know if these genetic variations can help predict ADRs and how they can be used to better adjust treatment. This study addresses these questions and will provide important insight of how a person’s genetics can affect the response to certain drugs, leading to better treatment of childhood ALL patients.
Dr. Florian Kuchenbauer
BC Cancer, Vancouver
MiR-193a-based LNP drug treatment for pediatric acute myeloid leukemia
Acute myeloid leukemia (AML) is a blood cancer with poor outcomes. Currently, treatment still relies on chemotherapies which have an impact on the physical and mental development of children.
COVID-19 and mRNA-based therapeutics used to treat it have changed the world. Key to their success was the encapsulation of mRNAs within liposomal nanoparticles (LNPs).
Dr. Kuchenbauer’s research group and others have recently highlighted the potential of microRNA (miRNA) encapsulated LNPs to target specific mutations in leukemias, with fewer side effects. The team’s previous data showed that miR-193a (a gene associated with cancer) is significantly decreased in pediatric normal karyotype AML (CN-AML). In CN-AML, it has been shown that engineered over-expression of miR-193a slowed down the development of AML.
An LNP-miR-193a-3p-based drug (INT-1B3) is currently being studied in a clinical trial for solid tumours and the researchers will be testing this drug in pediatric CN-AML models. They aim to pioneer novel LNP-miRNA-based formulations for the treatment of pediatric AML. This innovative approach will help to reduce the chemotherapy burden on children, improve treatment outcomes, and help to foster normal development in a frail and underserved population.
Funded in partnership with Kindred Foundation
Acute myeloid leukemia (AML) is a blood cancer with poor outcomes. Currently, treatment still relies on chemotherapies which have an impact on the physical and mental development of children.
COVID-19 and mRNA-based therapeutics used to treat it have changed the world. Key to their success was the encapsulation of mRNAs within liposomal nanoparticles (LNPs).
Dr. Kuchenbauer’s research group and others have recently highlighted the potential of microRNA (miRNA) encapsulated LNPs to target specific mutations in leukemias, with fewer side effects. The team’s previous data showed that miR-193a (a gene associated with cancer) is significantly decreased in pediatric normal karyotype AML (CN-AML). In CN-AML, it has been shown that engineered over-expression of miR-193a slowed down the development of AML.
An LNP-miR-193a-3p-based drug (INT-1B3) is currently being studied in a clinical trial for solid tumours and the researchers will be testing this drug in pediatric CN-AML models. They aim to pioneer novel LNP-miRNA-based formulations for the treatment of pediatric AML. This innovative approach will help to reduce the chemotherapy burden on children, improve treatment outcomes, and help to foster normal development in a frail and underserved population.
Funded in partnership with Kindred Foundation
Dr. Vincent-Philippe Lavallée
Centre Hospitalier Universitaire Sainte-Justine, Montreal
Understanding the behaviour of central nervous system-infiltrating cells in pediatric acute myeloid leukemia
Acute myeloid leukemias (AML) are hard-to-treat cancers that originate in the bone marrow following the development of mutations (changes) in normal blood stem cells. In approximately 25% of children diagnosed with AML, cancer cells migrate to the central nervous system (CNS) where they can potentially cause long-term neurological consequences. These patients need to be treated more intensively to prevent CNS relapse. However, the characteristics of the rare CNS infiltrating cells are very poorly described.
In this study, the researchers will evaluate if they can better diagnose CNS-infiltration in pediatric AML and further their understanding of this complication. They will assess whether a technique called single-cell RNA-sequencing can help in the diagnosis of CNS-infiltrating cells in pediatric AML, especially in cases where very few cells are identified by microscopic evaluation.
The study will determine whether single-cell RNA-sequencing can help identify those with pediatric AML with CNS infiltration, who could potentially benefit from more intense treatment. It will also provide a first exploration of gene expression and mutations specific to CNS infiltrating cells in this disease.
Acute myeloid leukemias (AML) are hard-to-treat cancers that originate in the bone marrow following the development of mutations (changes) in normal blood stem cells. In approximately 25% of children diagnosed with AML, cancer cells migrate to the central nervous system (CNS) where they can potentially cause long-term neurological consequences. These patients need to be treated more intensively to prevent CNS relapse. However, the characteristics of the rare CNS infiltrating cells are very poorly described.
In this study, the researchers will evaluate if they can better diagnose CNS-infiltration in pediatric AML and further their understanding of this complication. They will assess whether a technique called single-cell RNA-sequencing can help in the diagnosis of CNS-infiltrating cells in pediatric AML, especially in cases where very few cells are identified by microscopic evaluation.
The study will determine whether single-cell RNA-sequencing can help identify those with pediatric AML with CNS infiltration, who could potentially benefit from more intense treatment. It will also provide a first exploration of gene expression and mutations specific to CNS infiltrating cells in this disease.
Dr. Gregor Reid
University of British Columbia, Vancouver
Targeting the biology of hyperdiploid acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Hyperdiploid (HD) ALL accounts for about 20% of pediatric leukemia diagnoses each year and responds very well to current treatments.
This success, however, often obscures the reality that HD-ALL remains the largest single contributor to ALL relapse. Cure rates for children with relapsed HD-ALL are less than 50% and new treatment strategies are needed.
In this study, the researchers aim to investigate the biology of HD-ALL in order to identify new types of therapy. To achieve this, they will use a unique model which will enable them to perform previously difficult experiments to track leukemia development from its very beginning. This will allow the researchers to identify changes common to all the abnormal cells in HD-ALL. The results of this study could identify effective ways to reduce the incidence of HD-ALL relapse by eradicating the leukemia cells that are not sensitive to current treatments.
Acute lymphoblastic leukemia (ALL) is the most common cancer in children. Hyperdiploid (HD) ALL accounts for about 20% of pediatric leukemia diagnoses each year and responds very well to current treatments.
This success, however, often obscures the reality that HD-ALL remains the largest single contributor to ALL relapse. Cure rates for children with relapsed HD-ALL are less than 50% and new treatment strategies are needed.
In this study, the researchers aim to investigate the biology of HD-ALL in order to identify new types of therapy. To achieve this, they will use a unique model which will enable them to perform previously difficult experiments to track leukemia development from its very beginning. This will allow the researchers to identify changes common to all the abnormal cells in HD-ALL. The results of this study could identify effective ways to reduce the incidence of HD-ALL relapse by eradicating the leukemia cells that are not sensitive to current treatments.
Dr. Kirk Schultz
University of British Columbia, Vancouver
Increasing the safety of childhood blood stem cell transplant
Bone marrow transplantation (BMT) can cure blood cancers. While transplanting donor marrow has become substantially safer and more effective in the last few decades, its use is still limited because of the risk of a life-threatening, autoimmune complication called chronic graft-versus-host disease (cGvHD).
This complication occurs when the donor immune system attacks healthy tissues in the recipient. To learn more about who is at most at risk of developing cGvHD and which treatments are best-suited for each patient, the Canada-based Applied Biomarkers in Late Effects of Children and Adolescents with Cancer (ABLE) Team has been working to identify biomarkers (a biological molecule that signals a process, condition or disease). The ABLE studies have shown that the enzyme sCD13 is elevated in cGvHD.
In this project, the research team will investigate how sCD13 may affect immune cells and contribute to cGvHD. They will also study if the drug Bestatin (which inhibits sCD13) prevents development of cGvHD. If the team can show that inhibiting sCD13 can eliminate cGvHD they will be poised to start a clinical trial to determine if this approach can minimize the incidence and severity of cGvHD and make BMT a safer cure for children and adolescents.
Bone marrow transplantation (BMT) can cure blood cancers. While transplanting donor marrow has become substantially safer and more effective in the last few decades, its use is still limited because of the risk of a life-threatening, autoimmune complication called chronic graft-versus-host disease (cGvHD).
This complication occurs when the donor immune system attacks healthy tissues in the recipient. To learn more about who is at most at risk of developing cGvHD and which treatments are best-suited for each patient, the Canada-based Applied Biomarkers in Late Effects of Children and Adolescents with Cancer (ABLE) Team has been working to identify biomarkers (a biological molecule that signals a process, condition or disease). The ABLE studies have shown that the enzyme sCD13 is elevated in cGvHD.
In this project, the research team will investigate how sCD13 may affect immune cells and contribute to cGvHD. They will also study if the drug Bestatin (which inhibits sCD13) prevents development of cGvHD. If the team can show that inhibiting sCD13 can eliminate cGvHD they will be poised to start a clinical trial to determine if this approach can minimize the incidence and severity of cGvHD and make BMT a safer cure for children and adolescents.
Dr. Christian Steidl
BC Cancer, Vancouver
Decoding the tumour microenvironment of pediatric Hodgkin lymphoma
Hodgkin lymphoma (HL) is one of the most common cancers in children, adolescents and young adults (AYA). Although survival for HL patients has improved remarkably over the past decades, for those who have tumours that return after treatment, outcomes are less optimistic. Additionally, treatment-induced side effects, such as infertility, secondary cancers and heart disease, represent a serious issue for young HL survivors. For that reason, research into the biological markers pointing to the risk of treatment failure is a high priority with the aim of achieving longer survival while reducing side effects.
In this study, the research team will decode the tumour-microenvironment (TME) ecosystem in HL biopsy samples using a new technology called imaging mass cytometry (IMC). They will perform a comprehensive IMC analysis on biopsies which will allow them to uncover clinically meaningful variations in cell composition of the TME to better understand the biology of pediatric and AYA HL the aim is to translate biological findings into diagnostic tests that can be used in routine clinical practice for personalized treatments with higher cure rates and less toxicity.
Hodgkin lymphoma (HL) is one of the most common cancers in children, adolescents and young adults (AYA). Although survival for HL patients has improved remarkably over the past decades, for those who have tumours that return after treatment, outcomes are less optimistic. Additionally, treatment-induced side effects, such as infertility, secondary cancers and heart disease, represent a serious issue for young HL survivors. For that reason, research into the biological markers pointing to the risk of treatment failure is a high priority with the aim of achieving longer survival while reducing side effects.
In this study, the research team will decode the tumour-microenvironment (TME) ecosystem in HL biopsy samples using a new technology called imaging mass cytometry (IMC). They will perform a comprehensive IMC analysis on biopsies which will allow them to uncover clinically meaningful variations in cell composition of the TME to better understand the biology of pediatric and AYA HL the aim is to translate biological findings into diagnostic tests that can be used in routine clinical practice for personalized treatments with higher cure rates and less toxicity.
Clinician Scientist Fellow Awards
The Clinician Scientist Fellow Award encourages early-stage specialist clinicians to pursue a career in blood cancer research. This opportunity is designed to foster the acquisition of skills and independence to conduct research in blood cancers in the laboratory, in the clinical setting or at combined levels. This program is offered in partnership with the Canadian Institutes of Health Research (CIHR).
Dr. Waleed Alduaij
BC Cancer, Vancouver
Study of aggressive B-cell lymphoma genes to help improve treatments
Aggressive B-cell lymphoma is a cancer of the immune system that can develop rapidly and require urgent treatment. This project will use a detailed genetic analysis of lymphoma samples to help better predict which individuals will not respond to current treatments so that their treatment can be improved. The results will also be used to discover new treatments that target the genetic defects in these cancers.
Funded in partnership with the Canadian Institutes of Health Research – Institute of Cancer Research
Aggressive B-cell lymphoma is a cancer of the immune system that can develop rapidly and require urgent treatment. This project will use a detailed genetic analysis of lymphoma samples to help better predict which individuals will not respond to current treatments so that their treatment can be improved. The results will also be used to discover new treatments that target the genetic defects in these cancers.
Funded in partnership with the Canadian Institutes of Health Research – Institute of Cancer Research
Dr. Holly Lee
University of Calgary
Defining T cell intrinsic determinants of TCE mediated MM cytotoxicity
Cancer immunotherapies that engage and redirect host T cells to target tumours have revolutionized the field of oncology. T cells play an essential role in controlling the growth of cancer cells. In multiple myeloma (MM), when T cells malfunction, it allows the uncontrolled spread of abnormal plasma cells.
Targeting the B-cell maturation antigen (BCMA) of plasma cells with chimeric antigen receptor T cells (CAR-T) or bispecific T cell engagers (TCE) has been shown to effectively treat advanced myeloma.
Despite these encouraging clinical results, these new treatments do not work for all patients. This highlights the importance of understanding how MM cells are evading these immunotherapies.
The goal of this project is to perform an in-depth examination of T-cells in MM myeloma.
This will lead to an improved understanding of the bone marrow of those with MM who respond to TCE therapy versus those whose MM does not respond to treatment. This knowledge can be used to help in making decisions on the timing and selection of treatment.
Cancer immunotherapies that engage and redirect host T cells to target tumours have revolutionized the field of oncology. T cells play an essential role in controlling the growth of cancer cells. In multiple myeloma (MM), when T cells malfunction, it allows the uncontrolled spread of abnormal plasma cells.
Targeting the B-cell maturation antigen (BCMA) of plasma cells with chimeric antigen receptor T cells (CAR-T) or bispecific T cell engagers (TCE) has been shown to effectively treat advanced myeloma.
Despite these encouraging clinical results, these new treatments do not work for all patients. This highlights the importance of understanding how MM cells are evading these immunotherapies.
The goal of this project is to perform an in-depth examination of T-cells in MM myeloma.
This will lead to an improved understanding of the bone marrow of those with MM who respond to TCE therapy versus those whose MM does not respond to treatment. This knowledge can be used to help in making decisions on the timing and selection of treatment.
Dr. Andrew Lytle
BC Cancer, Vancouver
Profiling the gene changes in follicular lymphoma to predict disease development and guide therapies
Follicular lymphoma (FL) is a common blood cancer and its development can vary significantly. Reliable tools (biomarkers) to identify those individuals with FL at higher risk of death from lymphoma are needed to provide the most effective care. Using sophisticated techniques to profile the genetic changes in FL and interactions between FL cells and normal cells, the researchers aim to develop new ways to predict FL disease behaviour and guide targeted therapies.
Follicular lymphoma (FL) is a common blood cancer and its development can vary significantly. Reliable tools (biomarkers) to identify those individuals with FL at higher risk of death from lymphoma are needed to provide the most effective care. Using sophisticated techniques to profile the genetic changes in FL and interactions between FL cells and normal cells, the researchers aim to develop new ways to predict FL disease behaviour and guide targeted therapies.
Dr. Robert Vanner
University Health Network, Toronto
Role of the mutated blood stem cell in anti-tumour immunity
When a blood stem cell, which can develop into different types of blood cells, starts producing mutated cells it is a condition called clonal hematopoiesis. The research team has discovered that one type of clonal hematopoiesis triggers the immune system to help fight cancer. They will test whether clonal hematopoiesis can help to identify those who respond to immunotherapy and define how it supercharges immunotherapy treatments. The findings could help match future patients to the most effective therapies and may lay the foundation for new immunotherapies for cancers, including leukemia and lymphoma.
Funded in partnership with the Canadian Institutes of Health Research – Institute of Cancer Research
When a blood stem cell, which can develop into different types of blood cells, starts producing mutated cells it is a condition called clonal hematopoiesis. The research team has discovered that one type of clonal hematopoiesis triggers the immune system to help fight cancer. They will test whether clonal hematopoiesis can help to identify those who respond to immunotherapy and define how it supercharges immunotherapy treatments. The findings could help match future patients to the most effective therapies and may lay the foundation for new immunotherapies for cancers, including leukemia and lymphoma.
Funded in partnership with the Canadian Institutes of Health Research – Institute of Cancer Research
Operating Grants
The LLSC is pleased to partner with Cancer Research Society to co-fund ten (10) blood cancer projects from the CRS 2021 Operating Grant Competition.
The grants that focus on advancing the understanding of and improving treatment options for all blood cancers.
Steven Chan
University Health Network
Targeting SYK signaling to overcome resistance to IDH inhibitors in acute myeloid leukemia
Acute myeloid leukemia (AML) is an aggressive blood cancer that responds poorly to current treatments. A new class of medications known as IDH inhibitors have recently been approved for the treatment of AML patients with mutations in genes called IDH1 and IDH2. Although these drugs are effective for some patients, many do not respond at all or lose their response over time. There is a need to understand why this happens and find ways to make these drugs more effective. We recently discovered that activation of a protein called SYK may be the reason why some AML patients do not respond to IDH inhibitors. In our research proposal, we will build on these findings by studying how changes in SYK activation affect the response of human AML cells to IDH inhibitors. We will also study if blocking SYK activation with another drug can make AML cells respond better to IDH inhibitors. We anticipate that our findings will help discover new ways to improve the efficacy of IDH inhibitors and outcomes of AML patients.
Acute myeloid leukemia (AML) is an aggressive blood cancer that responds poorly to current treatments. A new class of medications known as IDH inhibitors have recently been approved for the treatment of AML patients with mutations in genes called IDH1 and IDH2. Although these drugs are effective for some patients, many do not respond at all or lose their response over time. There is a need to understand why this happens and find ways to make these drugs more effective. We recently discovered that activation of a protein called SYK may be the reason why some AML patients do not respond to IDH inhibitors. In our research proposal, we will build on these findings by studying how changes in SYK activation affect the response of human AML cells to IDH inhibitors. We will also study if blocking SYK activation with another drug can make AML cells respond better to IDH inhibitors. We anticipate that our findings will help discover new ways to improve the efficacy of IDH inhibitors and outcomes of AML patients.
TorontoON
Canada
Etienne Gagnon
Université de Montréal
Optimizing and benchmarking novel modular CARs targeting leukemia.
The latest advancements in cancer therapies weaponize the patient’s own immune system fight the cancer cells as if they were foreign invaders such bacteria or viruses. One current therapy uses chimeric antigen receptor (CAR), which enables the immune cells to recognize cancer cells, leading to the destruction of the targeted cells. These therapies shown great success in treating patients with various types of leukemia, but this approach has been fraught with severe side effects. The novel CAR architectures proposed in this research address the shortcomings observed for current CAR technology, which should lead to a significant improvement in tumor clearing while minimizing unwanted side effects and complications. Ultimately, the added efficiency and safety of these new mCARs (modular CARs) will not only improve patient outcomes, but has the potential to reduce bed-side costs typically associated with complications to CAR therapy to make it amendable to government-subsidized healthcare plans such as those found in Canada.
The latest advancements in cancer therapies weaponize the patient’s own immune system fight the cancer cells as if they were foreign invaders such bacteria or viruses. One current therapy uses chimeric antigen receptor (CAR), which enables the immune cells to recognize cancer cells, leading to the destruction of the targeted cells. These therapies shown great success in treating patients with various types of leukemia, but this approach has been fraught with severe side effects. The novel CAR architectures proposed in this research address the shortcomings observed for current CAR technology, which should lead to a significant improvement in tumor clearing while minimizing unwanted side effects and complications. Ultimately, the added efficiency and safety of these new mCARs (modular CARs) will not only improve patient outcomes, but has the potential to reduce bed-side costs typically associated with complications to CAR therapy to make it amendable to government-subsidized healthcare plans such as those found in Canada.
MontrealQC
Canada
Martin Guimond
Centre de Recherche, Hôpital Maisonneuve-Rosemont
The effect of EGFL7 on graft-versus-host disease and graft versus leukemia effect
Chemotherapy with stem cell transplantation is often the only curative treatment for leukemia patients. Unfortunately, white blood cells contained in the stem cell transplant can attack the patient. This condition is serious, and several patients die every year. Drugs currently used to treat this condition are not always effective. In addition, these treatments induce profound immunosuppression which increase the risk of developing lethal infectious complications. EGFL7 has the potential to decrease unwanted side effects of bone marrow transplantation. This proposal seeks to investigate the novel molecule (EGF7) to improve the safety of bone marrow transplantation to cure leukemia.
Chemotherapy with stem cell transplantation is often the only curative treatment for leukemia patients. Unfortunately, white blood cells contained in the stem cell transplant can attack the patient. This condition is serious, and several patients die every year. Drugs currently used to treat this condition are not always effective. In addition, these treatments induce profound immunosuppression which increase the risk of developing lethal infectious complications. EGFL7 has the potential to decrease unwanted side effects of bone marrow transplantation. This proposal seeks to investigate the novel molecule (EGF7) to improve the safety of bone marrow transplantation to cure leukemia.
MontrealQC
Canada
Patrick Gunning
Governing Council of the University of Toronto
Development of selective HDAC inhibitors for the treatment of hematological malignancies
Treatments and outcomes for patients with blood cancers have substantially improved over the past decade due to the development of new drugs. However, a large cohort of patients often develop resistance following continued drug treatment, leading to poor clinical outcomes. One emerging approach is to target a protein called histone deacetylase 6, (HDAC6) which has shown to mediate chemotherapeutic resistance and can re-sensitize tumors to standard-of-care treatments. Although, there are 4 FDA-approved drugs that target HDAC6 on the market, they are unselective and target HDAC6 in addition to another 10 similar HDAC proteins. This leads to severe toxicities in patients. Newer drugs in Phase I and II clinical trials, have shown modest 5-6 fold selectivity for HDAC6. Here, we have synthesized small molecule inhibitors that have shown exquisite HDAC6 selectivity (>150 fold). We aim to expand on our current chemical scaffolds to further develop their drug-like properties, and evaluate their efficacy in blood cancer models to design better treatments and hopefully improve patient outcomes.
Treatments and outcomes for patients with blood cancers have substantially improved over the past decade due to the development of new drugs. However, a large cohort of patients often develop resistance following continued drug treatment, leading to poor clinical outcomes. One emerging approach is to target a protein called histone deacetylase 6, (HDAC6) which has shown to mediate chemotherapeutic resistance and can re-sensitize tumors to standard-of-care treatments. Although, there are 4 FDA-approved drugs that target HDAC6 on the market, they are unselective and target HDAC6 in addition to another 10 similar HDAC proteins. This leads to severe toxicities in patients. Newer drugs in Phase I and II clinical trials, have shown modest 5-6 fold selectivity for HDAC6. Here, we have synthesized small molecule inhibitors that have shown exquisite HDAC6 selectivity (>150 fold). We aim to expand on our current chemical scaffolds to further develop their drug-like properties, and evaluate their efficacy in blood cancer models to design better treatments and hopefully improve patient outcomes.
TorontoON
Canada
Valentin Jaumouillé
Simon Fraser University
Understanding and exploiting the mechanobiology of macrophages to promote clearance of lymphoma cells by phagocytosis
Cancer immunotherapies are being developed as a new type of treatment that act by boosting the natural capacities of the immune system and directing it to destroy tumors. Among the different types of cells comprising the immune system, macrophages have the capacity to eliminate microbes and cancer cells by engulfing and digesting them. However, in most patients, macrophages do not eliminate cancer cells and instead put a brake on the activity of the immune system against the tumor. Macrophages identify which cell to eliminate by testing their molecular and physical characteristics. Recent evidence suggests that the physical characteristics of lymphoma cells help them escape engulfment by macrophages. The goal of this project is to understand how macrophages could overcome the physical constraints involved in engulfment of lymphoma cells. Specifically, we aim to identify the two critical properties of macrophages for the engulfment of lymphoma cells: force transmission and cellular deformation. Understanding these molecular mechanisms will provide new strategies for the development of more effective immunotherapies that promote the eradication of lymphoma by macrophages.
Cancer immunotherapies are being developed as a new type of treatment that act by boosting the natural capacities of the immune system and directing it to destroy tumors. Among the different types of cells comprising the immune system, macrophages have the capacity to eliminate microbes and cancer cells by engulfing and digesting them. However, in most patients, macrophages do not eliminate cancer cells and instead put a brake on the activity of the immune system against the tumor. Macrophages identify which cell to eliminate by testing their molecular and physical characteristics. Recent evidence suggests that the physical characteristics of lymphoma cells help them escape engulfment by macrophages. The goal of this project is to understand how macrophages could overcome the physical constraints involved in engulfment of lymphoma cells. Specifically, we aim to identify the two critical properties of macrophages for the engulfment of lymphoma cells: force transmission and cellular deformation. Understanding these molecular mechanisms will provide new strategies for the development of more effective immunotherapies that promote the eradication of lymphoma by macrophages.
BurnabyBC
Canada
Eric Milot
Hopital Maisoneuve-Rosemont, centre de recherche
Influence of IKAROS on treatment response in Acute Lymphocytic Leukemia
The transcription factor Ikaros is frequently disrupted in B and T cell acute lymphoblastic leukemia (ALL) and is associated with poor clinical outcome. Chemotherapy drugs used in ALL treatment kill cancer cells by damaging their genetic material (DNA). Our previous results suggest that Ikaros interacts with a genomic structure call R-loop and Ikaros mutation results in the accumulation of R-loop, which can be toxic. We want to define whether Ikaros disruption promotes the accumulation of R-loops in ALL cells by investigating the mechanisms involved, protein partners of Ikaros and the effect of Ikaros disruption on genomic R-loops. We will address whether the disruption of Ikaros influences R-loop accumulation and genomic stability, and hence, could be fundamental to determine the therapeutic regimen to cure ALL characterized by the disruption of Ikaros.
The transcription factor Ikaros is frequently disrupted in B and T cell acute lymphoblastic leukemia (ALL) and is associated with poor clinical outcome. Chemotherapy drugs used in ALL treatment kill cancer cells by damaging their genetic material (DNA). Our previous results suggest that Ikaros interacts with a genomic structure call R-loop and Ikaros mutation results in the accumulation of R-loop, which can be toxic. We want to define whether Ikaros disruption promotes the accumulation of R-loops in ALL cells by investigating the mechanisms involved, protein partners of Ikaros and the effect of Ikaros disruption on genomic R-loops. We will address whether the disruption of Ikaros influences R-loop accumulation and genomic stability, and hence, could be fundamental to determine the therapeutic regimen to cure ALL characterized by the disruption of Ikaros.
MontrealQC
Canada
Jane McGlade
The Hospital for Sick Children
GADS dependent signaling networks in BCR-ABL driven leukemia.
Interactions between molecules inside cells transmit signals that control normal cell functions. Disruption to these normal signaling pathways are at the root of many human diseases. One well established genetic mutation that causes leukemia, gives rise to the production of a defective protein called BCR-ABL that disrupts normal cell behavior. The consequence is uncontrolled growth of certain blood cells that cause the diseases Chronic Myeloid Leukemia (CML) and in B-cell acute lymphoblastic leukemia (B-ALL). Drugs that inactivate the BCR-ABL protein are effective in the treatment for leukemia but in some patients the drug stops working because the leukemia cells become resistant to its effects over time. The goal of our research is to identify new target proteins that will lead to the development of drugs that can be used to improve treatment of patients with B-ALL and CML as well as patients whose leukemia has become resistant to BCR-ABL inhibiting drugs.
Interactions between molecules inside cells transmit signals that control normal cell functions. Disruption to these normal signaling pathways are at the root of many human diseases. One well established genetic mutation that causes leukemia, gives rise to the production of a defective protein called BCR-ABL that disrupts normal cell behavior. The consequence is uncontrolled growth of certain blood cells that cause the diseases Chronic Myeloid Leukemia (CML) and in B-cell acute lymphoblastic leukemia (B-ALL). Drugs that inactivate the BCR-ABL protein are effective in the treatment for leukemia but in some patients the drug stops working because the leukemia cells become resistant to its effects over time. The goal of our research is to identify new target proteins that will lead to the development of drugs that can be used to improve treatment of patients with B-ALL and CML as well as patients whose leukemia has become resistant to BCR-ABL inhibiting drugs.
TorontoON
Canada
Javier Di Noia
Montreal Clinical Research Institute (IRCM)
An orphan deaminase as a novel source of chemotherapy resistance in cancer
Cancer is a disease of uncontrolled cell proliferation, for which each cell must duplicate their genomic material. To replicate the genome, the cell must have sufficient availability of the four building blocks (or deoxynucleotides) that make the DNA. One of the deoxynucleotides, dTTP, is made in a special way and is limiting for cell proliferation. Cancer cells are more sensitive to drugs that poison DNA replication because of their rapid proliferation. A category of compounds very commonly used for this purpose resemble another one of the deoxynucleotides. When these compounds are incorporated into the DNA, they stop replication and kill the cell. The efficacy of this treatment is limited by enzymes present in the cancer cells that inactivate the compounds. We have identified CDADC1, a new enzyme of unknown function that might be important for the proliferation of certain leukemia cells, by facilitating dTTP production. We also found that CDADC1 increases the resistance to at least one of these anti-cancer compounds (gemcitabine) in cancer cells cultured in the laboratory. We will investigate the mechanism by which CDADC1 affects the toxicity of gemcitabine and similar compounds. Inhibiting CDADC1 could eventually improve the efficacy of gemcitabine and similar compounds against cancer.
Cancer is a disease of uncontrolled cell proliferation, for which each cell must duplicate their genomic material. To replicate the genome, the cell must have sufficient availability of the four building blocks (or deoxynucleotides) that make the DNA. One of the deoxynucleotides, dTTP, is made in a special way and is limiting for cell proliferation. Cancer cells are more sensitive to drugs that poison DNA replication because of their rapid proliferation. A category of compounds very commonly used for this purpose resemble another one of the deoxynucleotides. When these compounds are incorporated into the DNA, they stop replication and kill the cell. The efficacy of this treatment is limited by enzymes present in the cancer cells that inactivate the compounds. We have identified CDADC1, a new enzyme of unknown function that might be important for the proliferation of certain leukemia cells, by facilitating dTTP production. We also found that CDADC1 increases the resistance to at least one of these anti-cancer compounds (gemcitabine) in cancer cells cultured in the laboratory. We will investigate the mechanism by which CDADC1 affects the toxicity of gemcitabine and similar compounds. Inhibiting CDADC1 could eventually improve the efficacy of gemcitabine and similar compounds against cancer.
MontrealQC
Canada
Moutih Rafei
Université de Montréal
Enhancing Endosome-to-Cytosol Import of Antigen to Augment Anti-tumoral Immunity
Dr. Rafei has been actively studying the biology of a bone marrow population subset known as mesenchymal stromal cells (MSCs). One of the main goals of Dr. Rafei’s group is to genetically engineer MSCs capable of mounting potent immune responses to eradicate established tumors while providing long-term protective memory protection. The data obtained so far clearly demonstrate that these engineered cells are superior to standard dendritic cells (the most powerful antigen presenting cell known so far) indicating that they can be effectively exploited for the formulation of new cellular-based cancer vaccines. Building on this success, the follow-up objective consists of further understanding the mechanism controlling the ability of these cells to effectively activate the immune system in order to design second or third generation cellular cancer vaccines.
Dr. Rafei has been actively studying the biology of a bone marrow population subset known as mesenchymal stromal cells (MSCs). One of the main goals of Dr. Rafei’s group is to genetically engineer MSCs capable of mounting potent immune responses to eradicate established tumors while providing long-term protective memory protection. The data obtained so far clearly demonstrate that these engineered cells are superior to standard dendritic cells (the most powerful antigen presenting cell known so far) indicating that they can be effectively exploited for the formulation of new cellular-based cancer vaccines. Building on this success, the follow-up objective consists of further understanding the mechanism controlling the ability of these cells to effectively activate the immune system in order to design second or third generation cellular cancer vaccines.
MontrealQC
Canada
Francis Rodier
Centre de Recherche du Centre Hospitalier de l'Université de Montréal
Evaluating new pharmacologically targetable molecular hallmarks of premature aging in childhood blood cancer survivors
Childhood acute lymphoblastic leukemia is a form of cancer affecting mostly children under 15 years old. Sixty years ago, only 3% of children survived the disease. Thanks to scientific research, nowadays over 80% of children are cured, but survivors suffer from severe late adverse effects reminiscent of premature aging symptoms. Evaluating this premature aging involves many clinical tests and a lifelong clinical follow-up. Improving this evaluation would greatly improve survivors’ quality of life. We developed a test which measures a molecular marker named TREC. It is faster, less invasive than current tests and can be done with a single blood sample. In our preliminary experiments, we show that TREC are an effective marker of both normal aging and leukemia treatment-induced premature aging. We aim to better understand the clinical relevance of TREC and to evaluate new experimental treatments targeting premature aging to lower side effects and ameliorate clinical follow-up for childhood acute lymphoblastic leukemia survivors.
Childhood acute lymphoblastic leukemia is a form of cancer affecting mostly children under 15 years old. Sixty years ago, only 3% of children survived the disease. Thanks to scientific research, nowadays over 80% of children are cured, but survivors suffer from severe late adverse effects reminiscent of premature aging symptoms. Evaluating this premature aging involves many clinical tests and a lifelong clinical follow-up. Improving this evaluation would greatly improve survivors’ quality of life. We developed a test which measures a molecular marker named TREC. It is faster, less invasive than current tests and can be done with a single blood sample. In our preliminary experiments, we show that TREC are an effective marker of both normal aging and leukemia treatment-induced premature aging. We aim to better understand the clinical relevance of TREC and to evaluate new experimental treatments targeting premature aging to lower side effects and ameliorate clinical follow-up for childhood acute lymphoblastic leukemia survivors.
MontrealQC
Canada
Canadian-Led Immunotherapies in Cancer: CLIC-1901
LLSC is partnering with BioCanRx to help Canadian scientist expand their ability to conduct clinical trials of CAR T therapy. BioCanRx, Canada’s Immunotherapy Network, is a network of scientists, clinicians, cancer stakeholders, academic institutions, NGOs and industry partners working together to accelerate the development of leading-edge immune oncology therapies for the benefit of patients.
Dr. Natasha Kekre
The Ottawa Hospital
Canadian-led clinical trial of made-in-Canada CAR T-cell therapy for relapsed leukemia and lymphoma
CAR T-cell therapy uses a patient’s own immune T cells to detect and kill cancer cells. The complex process involves extracting T cells from the blood and genetically modifying them in a lab to find and kill cancer cells. These supercharged cells are then put back into a patient’s bloodstream where they multiply and find and destroy cancer cells.
Until now, Canada has been without the laboratory facilities to modify these all-important T cells. BioCanRx’s Canadian-led Immunotherapies in Cancer (CLIC-01) trial is unique because it is the first ever to develop and manufacture CAR T cells in Canada. Currently, if a person is to receive CAR T therapy, their T cells are sent to a lab outside of Canada for manufacturing. The trial will help to expand the ability to manufacture made-in-Canada CAR T cells and, ultimately, improve access to this life-saving treatment.
Dr. Kekre has been leading the CLIC-01 trial, which treats patients with relapsed/refractory blood cancers. In this new study, Dr. Kekre has used facilities in Ottawa and Victoria to manufacture the CAR-T cells for this early phase clinical trial with patient sites in Ottawa and Vancouver.
CAR T-cell therapy uses a patient’s own immune T cells to detect and kill cancer cells. The complex process involves extracting T cells from the blood and genetically modifying them in a lab to find and kill cancer cells. These supercharged cells are then put back into a patient’s bloodstream where they multiply and find and destroy cancer cells.
Until now, Canada has been without the laboratory facilities to modify these all-important T cells. BioCanRx’s Canadian-led Immunotherapies in Cancer (CLIC-01) trial is unique because it is the first ever to develop and manufacture CAR T cells in Canada. Currently, if a person is to receive CAR T therapy, their T cells are sent to a lab outside of Canada for manufacturing. The trial will help to expand the ability to manufacture made-in-Canada CAR T cells and, ultimately, improve access to this life-saving treatment.
Dr. Kekre has been leading the CLIC-01 trial, which treats patients with relapsed/refractory blood cancers. In this new study, Dr. Kekre has used facilities in Ottawa and Victoria to manufacture the CAR-T cells for this early phase clinical trial with patient sites in Ottawa and Vancouver.
OttawaON
Canada
2021 Research Investment
Operating Grants
Our Operating Grants offer funding (up to $100,000/year) for two-years for basic research that contributes to the advancement of science aimed at preventing, detecting and treating blood cancers. These grants recognize scientists whose work will contribute to the tremendous momentum in blood cancer research and yield groundbreaking results in treating patients and extending lives.
Dr. Versha Banerji
CancerCare Manitoba
Draining the batteries: a novel approach to treatment strategies in CLL
Cancer cells, specifically chronic lymphocytic leukemia cells are charged with energy when compared to normal B-lymphocytes. We have identified that certain markers on the leukemia cells, such as one called ZAP 70, predicts which cells have higher energy levels. We do not, however, know what factors outside the cell or within the cells actually alter ZAP 70 to change the energy status of the cell. We believe learning this information is important for two main reasons: 1) It could be used to predict what doses of new drugs may best be used for patients to ensure they are working without side effects, and 2) Inform us how drugs should be combined to avoid side effects while maximizing the effect of treatment. By determining how to best assess energy changes in cancer cells under certain conditions, we can best learn about how different drugs “drain the batteries” of the leukemia cells.
Cancer cells, specifically chronic lymphocytic leukemia cells are charged with energy when compared to normal B-lymphocytes. We have identified that certain markers on the leukemia cells, such as one called ZAP 70, predicts which cells have higher energy levels. We do not, however, know what factors outside the cell or within the cells actually alter ZAP 70 to change the energy status of the cell. We believe learning this information is important for two main reasons: 1) It could be used to predict what doses of new drugs may best be used for patients to ensure they are working without side effects, and 2) Inform us how drugs should be combined to avoid side effects while maximizing the effect of treatment. By determining how to best assess energy changes in cancer cells under certain conditions, we can best learn about how different drugs “drain the batteries” of the leukemia cells.
WinnipegMB
Canada
Dr. Lambert Busque
Hôpital Maisonneuve-Rosemont
Role of inflammation in acquired clonal hematopoiesis in aging individuals
Aging is associated with the acquisition of small changes (mutations) in the genes of blood cells. Some of these mutations can give a growth advantage to the affected cells, which will outgrow the normal ones. This phenomenon is called Age-Related Clonal Hematopoiesis (ARCH). The presence of ARCH is associated with a 10-fold increased risk of developing a blood cancer such as leukemia, and it also doubles the risk of having a heart disease. This proposal will determine the role of inflammation as an initiator of ARCH but also as a factor of progression to cancer and/or cardiovascular diseases. Our results could lead to the development of a test allowing early identification of individuals at risk, and pave the way for the development of intervention strategies based on microbiota modification and/or anti-inflammatory treatment.
Aging is associated with the acquisition of small changes (mutations) in the genes of blood cells. Some of these mutations can give a growth advantage to the affected cells, which will outgrow the normal ones. This phenomenon is called Age-Related Clonal Hematopoiesis (ARCH). The presence of ARCH is associated with a 10-fold increased risk of developing a blood cancer such as leukemia, and it also doubles the risk of having a heart disease. This proposal will determine the role of inflammation as an initiator of ARCH but also as a factor of progression to cancer and/or cardiovascular diseases. Our results could lead to the development of a test allowing early identification of individuals at risk, and pave the way for the development of intervention strategies based on microbiota modification and/or anti-inflammatory treatment.
MontrealQC
Canada
Dr. Jean-Sébastien Delisle
Hôpital Maisonneuve-Rosemont
Improved T-cell expansion and differentiation for adoptive immunotherapy
The injection of immune cells (T-cells) grown in specialized laboratories can be very effective to treat blood cancers. Unfortunately, these immune cells can get “tired” and are less effective at killing cancer cells after their expansion in the laboratory. We have found that by blocking natural “brakes” on these cells, we can prepare large quantities of effective cancer-killing immune cells. We now seek to better manipulate these brakes to produce better cancer-fighting immune cells for therapy. This project is entirely oriented towards the treatment of blood cancers and will be relevant to all forms of T-cell immunotherapies. Based on our expertise translating innovative T-cell therapies in the clinic, we aim to provide better more effective cancer-killing T-cells to use as a treatment for blood cancers
The injection of immune cells (T-cells) grown in specialized laboratories can be very effective to treat blood cancers. Unfortunately, these immune cells can get “tired” and are less effective at killing cancer cells after their expansion in the laboratory. We have found that by blocking natural “brakes” on these cells, we can prepare large quantities of effective cancer-killing immune cells. We now seek to better manipulate these brakes to produce better cancer-fighting immune cells for therapy. This project is entirely oriented towards the treatment of blood cancers and will be relevant to all forms of T-cell immunotherapies. Based on our expertise translating innovative T-cell therapies in the clinic, we aim to provide better more effective cancer-killing T-cells to use as a treatment for blood cancers
MontrealQC
Canada
Dr. Spencer Gibson
CancerCare Manitoba
Understanding the role of exosomes/microvesicles in the CLL microenvironment
We are studying the most common form of adult leukemia called chronic lymphocytic leukemia (CLL). Though there are many new treatments available, there is still no cure for CLL. Cancer cells can release particles that contain material that act as messengers to the surrounding cells. We have found that CLL patients that have more particles in their blood have more aggressive disease. We will investigate if these particles are playing a role in the development of drug resistance. It is also possible that these particles could be changing the function of other cells in the body, creating an environment that makes it easier for the cancer cells to survive. Finally, we will use a 3D model of cellular tissues to see if blocking the release of these particles will increase the amount of cell death in the cancer cells. Drug resistance remains a significant clinical barrier to treat CLL patients. By understanding the role these particles play in promoting cell survival in CLL cells, effective therapeutic strategies could be developed to overcome drug resistance.
We are studying the most common form of adult leukemia called chronic lymphocytic leukemia (CLL). Though there are many new treatments available, there is still no cure for CLL. Cancer cells can release particles that contain material that act as messengers to the surrounding cells. We have found that CLL patients that have more particles in their blood have more aggressive disease. We will investigate if these particles are playing a role in the development of drug resistance. It is also possible that these particles could be changing the function of other cells in the body, creating an environment that makes it easier for the cancer cells to survive. Finally, we will use a 3D model of cellular tissues to see if blocking the release of these particles will increase the amount of cell death in the cancer cells. Drug resistance remains a significant clinical barrier to treat CLL patients. By understanding the role these particles play in promoting cell survival in CLL cells, effective therapeutic strategies could be developed to overcome drug resistance.
WinnipegMB
Canada
Dr. Aly Karsan
BC Cancer Agency
Bypassing resistance to lenalidomide in del(5q) MDS
Myelodysplastic syndromes (MDS) are a type of blood cancer that have poor outcomes and for which few therapeutic options exist. About 1/3 of MDS patients progress to an incurable acute leukemia, with the rest dying of bone marrow failure. One type of MDS (del(5q) MDS) is normally treated by a medicine called lenalidomide (LEN). However, more than half of these patients do not respond or stop responding to treatment, indicating a need for new therapies. Our goal is to determine whether MDS patients who are resistant to lenalidomide might benefit from blocking a cell signaling pathway called IGF1R. Our work will lead to the potential of new treatment options for LEN-resistant MDS patients
Myelodysplastic syndromes (MDS) are a type of blood cancer that have poor outcomes and for which few therapeutic options exist. About 1/3 of MDS patients progress to an incurable acute leukemia, with the rest dying of bone marrow failure. One type of MDS (del(5q) MDS) is normally treated by a medicine called lenalidomide (LEN). However, more than half of these patients do not respond or stop responding to treatment, indicating a need for new therapies. Our goal is to determine whether MDS patients who are resistant to lenalidomide might benefit from blocking a cell signaling pathway called IGF1R. Our work will lead to the potential of new treatment options for LEN-resistant MDS patients
VancouverBC
Canada
Dr. John Kuruvilla
University Health Network
Exploiting metabolic vulnerabilities in aggressive non-Hodgkin lymphoma
Non-Hodgkin lymphomas (NHLs) are the fifth most commonly diagnosed cancer in Canadians and the most prevalent of all the blood cancers. New treatment options are urgently needed for NHL in patients that have cancers that return following primary treatment. To date, novel drug development initiatives in NHL have been largely unsuccessful in identifying new agents to improve on standard of care therapies. It is known that aggressive lymphomas need a constant and increased supply of nutrients to fuel cell division and proliferation. In devising strategies to cut off nutrient supplies, we uncovered adaptations that allow lymphoma cells to survive leaner times. We believe that preventing access to the nutrient sources represents an attractive method to combat NHL. We have developed novel drugs that act by inhibiting lymphoma cells from adapting to stress for use as combination therapies thereby exploiting metabolic vulnerabilities.
Non-Hodgkin lymphomas (NHLs) are the fifth most commonly diagnosed cancer in Canadians and the most prevalent of all the blood cancers. New treatment options are urgently needed for NHL in patients that have cancers that return following primary treatment. To date, novel drug development initiatives in NHL have been largely unsuccessful in identifying new agents to improve on standard of care therapies. It is known that aggressive lymphomas need a constant and increased supply of nutrients to fuel cell division and proliferation. In devising strategies to cut off nutrient supplies, we uncovered adaptations that allow lymphoma cells to survive leaner times. We believe that preventing access to the nutrient sources represents an attractive method to combat NHL. We have developed novel drugs that act by inhibiting lymphoma cells from adapting to stress for use as combination therapies thereby exploiting metabolic vulnerabilities.
TorontoON
Canada
Dr. Robert Kridel
University Health Network
Enhancing epigenetic therapies in B-cell lymphoma
This proposal will focus on aggressive B-cell lymphoma, which represents the most common form of lymphoma in Canada, with over 4,000 new diagnoses per year. Identifying novel treatment strategies for these patients is a critical, unmet need, given that relapse occurs in 40% of patients and is often life-limiting. Our understanding of how lymphoma arises has significantly improved over the last decade. Novel drugs are now available that precisely target critical proteins that are important for lymphoma cells to proliferate and survive. However, lymphoma cells often find ways to develop resistance. Consequently, most novel drugs have relatively low response rates and, even when patients have responsive disease, the duration of the response can be short. In our research, we aim to identify optimal drug combinations as a means to more effectively treat lymphoma. We will focus on drugs that can be combined with inhibitors of two proteins, namely EZH2 and HDAC3. We will not only apply cutting-edge methods to identify novel combination partners, but we will also aim to understand the mechanisms that explain the synergy that we observe. Our ultimate goal is to translate findings herein into a clinical trial that can benefit patients.
This proposal will focus on aggressive B-cell lymphoma, which represents the most common form of lymphoma in Canada, with over 4,000 new diagnoses per year. Identifying novel treatment strategies for these patients is a critical, unmet need, given that relapse occurs in 40% of patients and is often life-limiting. Our understanding of how lymphoma arises has significantly improved over the last decade. Novel drugs are now available that precisely target critical proteins that are important for lymphoma cells to proliferate and survive. However, lymphoma cells often find ways to develop resistance. Consequently, most novel drugs have relatively low response rates and, even when patients have responsive disease, the duration of the response can be short. In our research, we aim to identify optimal drug combinations as a means to more effectively treat lymphoma. We will focus on drugs that can be combined with inhibitors of two proteins, namely EZH2 and HDAC3. We will not only apply cutting-edge methods to identify novel combination partners, but we will also aim to understand the mechanisms that explain the synergy that we observe. Our ultimate goal is to translate findings herein into a clinical trial that can benefit patients.
TorontoON
Canada
Dr. Florian Kuchenbauer
BC Cancer Agency
Therapeutic targeting of the miR-106a-363 cluster in acute myeloid leukemia
Despite improved therapies, the 5-year relative survival for acute myeloid leukemia (AML) is currently 21% in Canada, with especially unfavorable prognosis for elderly patients. Therefore, new treatments that target the root of AML, leukemic stem cells (LSCs), are necessary. The current standard of care in elderly patients with AML, a combination of Venetoclax and azacytidine, has significantly improved overall survival. However, one third of responders relapsed, suggesting incomplete eradication of LSCs and thus making further investigation critical. MicroRNAs (miRNAs) exert key functions in LSCs and their dysregulation affects prognosis and outcome in AML patients. Furthermore, modulation of miRNA levels has shown promising results in preclinical models. Here we explore targeting LSCs through inhibition of a cancer-causing microRNA cluster in combination with Venetoclax and azacytidine. The proposed combination potentially intensifies depletion of LSCs and therefore has clinical potential not only in AML but also in other cancers such as lymphomas, multiple myeloma and solid tumors.
Despite improved therapies, the 5-year relative survival for acute myeloid leukemia (AML) is currently 21% in Canada, with especially unfavorable prognosis for elderly patients. Therefore, new treatments that target the root of AML, leukemic stem cells (LSCs), are necessary. The current standard of care in elderly patients with AML, a combination of Venetoclax and azacytidine, has significantly improved overall survival. However, one third of responders relapsed, suggesting incomplete eradication of LSCs and thus making further investigation critical. MicroRNAs (miRNAs) exert key functions in LSCs and their dysregulation affects prognosis and outcome in AML patients. Furthermore, modulation of miRNA levels has shown promising results in preclinical models. Here we explore targeting LSCs through inhibition of a cancer-causing microRNA cluster in combination with Venetoclax and azacytidine. The proposed combination potentially intensifies depletion of LSCs and therefore has clinical potential not only in AML but also in other cancers such as lymphomas, multiple myeloma and solid tumors.
VancouverBC
Canada
Dr. Sabine Mai
University of Manitoba
Targeting telomere maintenance in Hodgkin’s lymphoma
Inside our cells our genes are arranged along twisted, double-stranded molecules of DNA called chromosomes. At the ends of the chromosomes are stretches of DNA called telomeres which protect our genetic data, make it possible for cells to divide, and hold some secrets to how we age and get cancer. Telomere length maintenance is critical for cell division and cell survival. Normally, when telomeres reach a critical length the cells stop dividing and start to deteriorate and die. In Hodgkin’s lymphoma, however, the cells activate a protein called telomerase that maintains telomere length and prevents cell death. In this project, we will explore how Hodgkin’s Lymphoma cells maintain telomere length and then target their telomere maintenance pathways to prevent growth of cancer cells. We expect that treatments that target telomere maintenance pathways present in all cells of HL patients may alter the current treatment outcome of HL.
Inside our cells our genes are arranged along twisted, double-stranded molecules of DNA called chromosomes. At the ends of the chromosomes are stretches of DNA called telomeres which protect our genetic data, make it possible for cells to divide, and hold some secrets to how we age and get cancer. Telomere length maintenance is critical for cell division and cell survival. Normally, when telomeres reach a critical length the cells stop dividing and start to deteriorate and die. In Hodgkin’s lymphoma, however, the cells activate a protein called telomerase that maintains telomere length and prevents cell death. In this project, we will explore how Hodgkin’s Lymphoma cells maintain telomere length and then target their telomere maintenance pathways to prevent growth of cancer cells. We expect that treatments that target telomere maintenance pathways present in all cells of HL patients may alter the current treatment outcome of HL.
WinnipegMB
Canada
Dr. Koren Mann
Sir Mortimer B. Davis-Jewish General Hospital
STAT6 mutations in relapsed/refractory diffuse large B cell lymphoma
Lymphoma is a cancer of the lymphocytes that can be treated with chemotherapy, but is often fatal once resistance develops. We profiled mutations in one type of relapsed lymphoma, diffuse large B cell lymphoma (DLBCL). Here we found that the protein STAT6 is more frequently mutated in relapsed samples than those taken when the disease is first diagnosed. STAT6 is a protein that binds DNA and controls genes important in lymphocyte survival. In our preliminary experiments, we found that cells with these mutations grow faster. This has led us to try to understand how mutated STAT6 leads to increased cancer cell growth. We will then test whether cells with the mutant STAT6 protein relapse more quickly following treatment with chemotherapy. Furthermore, we think that these tumors may respond to a new class of drugs targeting this pathway alone or in combination with chemotherapy. We believe that this mutant STAT6 protein is a marker for tumors who will not response well to chemotherapy, but also a marker for those tumors that might respond to these STAT6-targeted therapies.
Lymphoma is a cancer of the lymphocytes that can be treated with chemotherapy, but is often fatal once resistance develops. We profiled mutations in one type of relapsed lymphoma, diffuse large B cell lymphoma (DLBCL). Here we found that the protein STAT6 is more frequently mutated in relapsed samples than those taken when the disease is first diagnosed. STAT6 is a protein that binds DNA and controls genes important in lymphocyte survival. In our preliminary experiments, we found that cells with these mutations grow faster. This has led us to try to understand how mutated STAT6 leads to increased cancer cell growth. We will then test whether cells with the mutant STAT6 protein relapse more quickly following treatment with chemotherapy. Furthermore, we think that these tumors may respond to a new class of drugs targeting this pathway alone or in combination with chemotherapy. We believe that this mutant STAT6 protein is a marker for tumors who will not response well to chemotherapy, but also a marker for those tumors that might respond to these STAT6-targeted therapies.
MontrealQC
Canada
Dr. Mark Minden
University Health Network
Exploration of nanopore sequencing in the diagnosis and prognosis of AML
Many Acute Myeloid Leukemia (AML) subtypes consistently swap between the same chromosomes (called a translocation). At the time of diagnosis, the translocation is identified and can be monitored after chemotherapy to guide further treatment. This is called residual disease monitoring (RDM). A subtype of leukemia associated with translocations is Mixed Lineage Leukemia (MLL). In this project we are using MLL as a model to identify chromosomal translocations in acute leukemia. Diagnosis can be complicated and there is no established test for RDM in MLL leukemia. Our first aim is to use a novel technology called nanopore sequencing to identify chromosomal translocations involving the MLL1 gene. Our second aim is to use the nanopore sequencing results to develop patient specific probes for residual disease monitoring. If successful, this project will potentially allow us to develop a patient specific approach for residual disease monitoring in many diseases, not just AML.
Many Acute Myeloid Leukemia (AML) subtypes consistently swap between the same chromosomes (called a translocation). At the time of diagnosis, the translocation is identified and can be monitored after chemotherapy to guide further treatment. This is called residual disease monitoring (RDM). A subtype of leukemia associated with translocations is Mixed Lineage Leukemia (MLL). In this project we are using MLL as a model to identify chromosomal translocations in acute leukemia. Diagnosis can be complicated and there is no established test for RDM in MLL leukemia. Our first aim is to use a novel technology called nanopore sequencing to identify chromosomal translocations involving the MLL1 gene. Our second aim is to use the nanopore sequencing results to develop patient specific probes for residual disease monitoring. If successful, this project will potentially allow us to develop a patient specific approach for residual disease monitoring in many diseases, not just AML.
TorontoON
Canada
Dr. Anastasia Nijnik
McGill University
Exploring MYSM1 as a potential drug-target for cMYC-driven B cell lymphoma
cMYC is an important regulator of gene expression and abnormal increase in cMYC activity is a major cause of cancer. In recent work we demonstrated that cMYC works together with another protein MYSM1 in the regulation of gene expression in the blood and immune systems. Loss of MYSM1 therefore can protect mice from cancers of the blood and immune system. The molecular mechanisms involved in the MYSM1 and cMYC interaction will be analysed in our proposed project. The long term goal is to determine whether inhibition of MYSM1 will also inhibit cMYC activity, and thus provide another potential treatment option.
cMYC is an important regulator of gene expression and abnormal increase in cMYC activity is a major cause of cancer. In recent work we demonstrated that cMYC works together with another protein MYSM1 in the regulation of gene expression in the blood and immune systems. Loss of MYSM1 therefore can protect mice from cancers of the blood and immune system. The molecular mechanisms involved in the MYSM1 and cMYC interaction will be analysed in our proposed project. The long term goal is to determine whether inhibition of MYSM1 will also inhibit cMYC activity, and thus provide another potential treatment option.
MontrealQC
Canada
Dr. Gilles André Robichaud
Université de Moncton
Platelet-packaged organelles: A novel outsourcing of cancer modulators
Inflammation is tightly linked with the development and progression of cancer. Among the inflammatory components participating in these processes are platelet cells. Platelets, initially discovered as clotting agents, are the second most abundant circulating blood cells in the human body. Interestingly, platelets also shed small vesicles (similar to escape pods) which package biologically active molecules. We have recently identified a new type of these vesicles, termed mitoMPs. These mitoMPs contain mitochondria which are known as the power and energy producing components of every cell. Our preliminary results show that mitoMPs bind and get enveloped by leukemia cells to transfer their content (mitochondria). As a result, these cancer cells have greater viability and have increased resistance to cellular death. We believe that mitoMPs represent important cancer modulators which will result in increased disease progression. In this study, we propose to define the significance of mitoMPs in chronic lymphocytic leukemia (CLL). Most importantly, we will determine the disease mechanisms which will then allow for the development of new strategic therapeutic approaches.
Funded in partnership with the New Brunswick Health Research Foundation (NBHRF).
Inflammation is tightly linked with the development and progression of cancer. Among the inflammatory components participating in these processes are platelet cells. Platelets, initially discovered as clotting agents, are the second most abundant circulating blood cells in the human body. Interestingly, platelets also shed small vesicles (similar to escape pods) which package biologically active molecules. We have recently identified a new type of these vesicles, termed mitoMPs. These mitoMPs contain mitochondria which are known as the power and energy producing components of every cell. Our preliminary results show that mitoMPs bind and get enveloped by leukemia cells to transfer their content (mitochondria). As a result, these cancer cells have greater viability and have increased resistance to cellular death. We believe that mitoMPs represent important cancer modulators which will result in increased disease progression. In this study, we propose to define the significance of mitoMPs in chronic lymphocytic leukemia (CLL). Most importantly, we will determine the disease mechanisms which will then allow for the development of new strategic therapeutic approaches.
Funded in partnership with the New Brunswick Health Research Foundation (NBHRF).
MonctonNB
Canada
Dr. Aaron Schimmer
University Health Network
The Beer Store Special Recognition Award Recipient 2019
Targeting the ubiquitin E1 ligase, UBA1, in AML
TAK-243 is a new drug that blocks the cell’s garbage disposal system. We have shown that TAK-243 kills AML cells in culture and mouse models while sparing normal cells. Based on these data, we propose a clinical trial of TAK-243 in patients with refractory AML. In support of this clinical trial, we will develop a laboratory-based test to determine whether TAK-243 can bind and inhibit its target. We will also investigate mechanisms by which cells become resistant to TAK-243. Finally, we will test new drug combinations that could enhance the ability of TAK-243 to kill AML cells while continuing to spare normal cells.
Targeting the ubiquitin E1 ligase, UBA1, in AML
TAK-243 is a new drug that blocks the cell’s garbage disposal system. We have shown that TAK-243 kills AML cells in culture and mouse models while sparing normal cells. Based on these data, we propose a clinical trial of TAK-243 in patients with refractory AML. In support of this clinical trial, we will develop a laboratory-based test to determine whether TAK-243 can bind and inhibit its target. We will also investigate mechanisms by which cells become resistant to TAK-243. Finally, we will test new drug combinations that could enhance the ability of TAK-243 to kill AML cells while continuing to spare normal cells.
TorontoON
Canada
Dr. Christian Steidl
BC Cancer Agency
PRAME alterations in DLBCL: Clinical and functional significance
Lymphomas are the 5th most common cancers in Canada. The current standard of care in many B cell lymphomas consists of chemotherapy and therapeutic monoclonal antibodies, and has significantly improved patient outcomes over the past 15 years. A large proportion of patients, however, suffer from refractory or relapsed disease. Therefore, the development of new therapeutic strategies for these patients represents an important unmet clinical need. We will investigate the roles of a new gene, PRAME, which is frequently deleted in patient’s tumors. However, the functional role of PRAME down regulation remains unknown. We will study how these deletions lead to lymphoma formation and how tumor cells escape from the patients’ own immune system surveillance, thus aiding in the development of new therapeutic avenues to simultaneously treat the tumor and the host.
Lymphomas are the 5th most common cancers in Canada. The current standard of care in many B cell lymphomas consists of chemotherapy and therapeutic monoclonal antibodies, and has significantly improved patient outcomes over the past 15 years. A large proportion of patients, however, suffer from refractory or relapsed disease. Therefore, the development of new therapeutic strategies for these patients represents an important unmet clinical need. We will investigate the roles of a new gene, PRAME, which is frequently deleted in patient’s tumors. However, the functional role of PRAME down regulation remains unknown. We will study how these deletions lead to lymphoma formation and how tumor cells escape from the patients’ own immune system surveillance, thus aiding in the development of new therapeutic avenues to simultaneously treat the tumor and the host.
Dr. Thai-Hoa Tran
CHU Sainte-Justine
Diagnosis, prognosis and novel therapy for Ph-like ALL in Canada
Co-applicants: Dr. James Whitlock, Dr. Sonia Cellot, Dr. Daniel Sinnett, Dr. Stephen Couban
While cure rates for childhood acute lymphoblastic leukemia (ALL) have improved significantly in the current era, relapse remains the most common cause of treatment failure and death. Teenagers and young adults with ALL have a worse outcome compared to younger children. Advances in cancer genetics have recently made several important discoveries, such as the identification of a particular group of patients who display a “genetic signature” similar to that of Philadelphia (Ph) chromosome-positive ALL but lacking the Ph chromosome. This is known as Ph-like ALL, and comprises approximately 15% of childhood ALL and over 25% among adults with ALL. Despite modern chemotherapy regimens, this group has poor survival rates compared to those without the “Ph-like” signature. Testing for Ph-like ALL remains limited in Canada and about 500 ALL patients do not have access to such testing each year. Given the poor prognosis and the possibility for outcome improvement, the main goal of this study is to develop a national screening program for Ph-like ALL using a novel sequencing technology. This screening will allow identifying Ph-like ALL patients who could benefit from the addition of TKI in combination with conventional chemotherapy in order to improve their outcomes.
Co-applicants: Dr. James Whitlock, Dr. Sonia Cellot, Dr. Daniel Sinnett, Dr. Stephen Couban
While cure rates for childhood acute lymphoblastic leukemia (ALL) have improved significantly in the current era, relapse remains the most common cause of treatment failure and death. Teenagers and young adults with ALL have a worse outcome compared to younger children. Advances in cancer genetics have recently made several important discoveries, such as the identification of a particular group of patients who display a “genetic signature” similar to that of Philadelphia (Ph) chromosome-positive ALL but lacking the Ph chromosome. This is known as Ph-like ALL, and comprises approximately 15% of childhood ALL and over 25% among adults with ALL. Despite modern chemotherapy regimens, this group has poor survival rates compared to those without the “Ph-like” signature. Testing for Ph-like ALL remains limited in Canada and about 500 ALL patients do not have access to such testing each year. Given the poor prognosis and the possibility for outcome improvement, the main goal of this study is to develop a national screening program for Ph-like ALL using a novel sequencing technology. This screening will allow identifying Ph-like ALL patients who could benefit from the addition of TKI in combination with conventional chemotherapy in order to improve their outcomes.
MontrealQC
Canada
Dr. Rosanna Weksberg
The Hospital for Sick Children
Co-applicant: Dr. Hans Hitzler
Late neurocognitive deficits in ALL survivors: DNA methylation biomarkers
Treatment of childhood leukemia is very effective; however, treatment can interfere with normal brain development in up to 50% of children treated. Brain functions such as attention, memory and intelligence can be affected leading to problems with learning and social skills. Importantly, these effects may only appear years after treatment has ended and are therefore called late effects. Our recent research suggests that patterns in epigenetic markers, i.e. changes to the DNA that controls whether genes are turned on or off, can help us understand how late effects develop in leukemia survivors. These epigenetic markers are stable over the years following treatment and have the potential to be used as a predictive tool for damaging effects on brain development. Our study aims to identify epigenetic markers in bone marrow cells collected during routine testing early in chemotherapy treatment to learn more about the possible causes of late effects. This information could help us predict which children are most susceptible to late effects. Additionally, these findings will enable the advancement of our understanding of the mechanisms of late effects, the development of early biomarkers, and the potential for early more personalized interventions.
Late neurocognitive deficits in ALL survivors: DNA methylation biomarkers
Treatment of childhood leukemia is very effective; however, treatment can interfere with normal brain development in up to 50% of children treated. Brain functions such as attention, memory and intelligence can be affected leading to problems with learning and social skills. Importantly, these effects may only appear years after treatment has ended and are therefore called late effects. Our recent research suggests that patterns in epigenetic markers, i.e. changes to the DNA that controls whether genes are turned on or off, can help us understand how late effects develop in leukemia survivors. These epigenetic markers are stable over the years following treatment and have the potential to be used as a predictive tool for damaging effects on brain development. Our study aims to identify epigenetic markers in bone marrow cells collected during routine testing early in chemotherapy treatment to learn more about the possible causes of late effects. This information could help us predict which children are most susceptible to late effects. Additionally, these findings will enable the advancement of our understanding of the mechanisms of late effects, the development of early biomarkers, and the potential for early more personalized interventions.
TorontoON
Canada
Dr. Peter W. Zandstra
University of British Columbia
Engineering proT-cells from stem cells for adoptive cell immunotherapy
In current CAR-T cell therapies, mature T-cells are collected from the patient’s blood, engineered to kill leukemia and lymphoma cells, and transplanted back into the patient. Successful implementation of this strategy is limited by high treatment costs, low cell yields, and long-term safety concerns. Many CAR T-cells recognize both cancerous and healthy cells, causing undesirable side effects. A ‘universal’ source of progenitor (pro) T-cells engineered to target certain cancer cells could be transplanted into the patient where they would develop into mature T-cells that would be tolerated by the patient’s immune system, thus minimizing the potential side effects. We have developed a way to grow proT-cells from stem cells and aim to demonstrate that CAR proT-cells are an effective way to treat blood cancers. Optimization of CAR-proT therapy should reduce targeting of healthy tissue, reduce side effects, and increase potency against many types of leukemia and lymphoma. Furthermore, development of proT- cells would allow for scalable production of ‘off the shelf’ cancer immunotherapies which would result in lower costs for patients.
In current CAR-T cell therapies, mature T-cells are collected from the patient’s blood, engineered to kill leukemia and lymphoma cells, and transplanted back into the patient. Successful implementation of this strategy is limited by high treatment costs, low cell yields, and long-term safety concerns. Many CAR T-cells recognize both cancerous and healthy cells, causing undesirable side effects. A ‘universal’ source of progenitor (pro) T-cells engineered to target certain cancer cells could be transplanted into the patient where they would develop into mature T-cells that would be tolerated by the patient’s immune system, thus minimizing the potential side effects. We have developed a way to grow proT-cells from stem cells and aim to demonstrate that CAR proT-cells are an effective way to treat blood cancers. Optimization of CAR-proT therapy should reduce targeting of healthy tissue, reduce side effects, and increase potency against many types of leukemia and lymphoma. Furthermore, development of proT- cells would allow for scalable production of ‘off the shelf’ cancer immunotherapies which would result in lower costs for patients.
VancouverBC
Canada
2020 Clinician Scientist Fellow Award (in partnership with CIHR)
The intent of the Clinician Scientist Fellow Award is to encourage early-stage specialist clinicians to pursue a career in blood cancer research. This opportunity is designed to foster the acquisition of skills and independence to conduct research in blood cancers at the laboratory, clinical or combined levels.
The Leukemia & Lymphoma Society of Canada, in partnership with the Canadian Institutes of Health Research (CIHR), is pleased to announce the recipient of the 2020 Clinician Scientist Fellow Award, Dr. Ryan Stubbins.
Dr. Ryan Stubbins
University of British Columbia
Precision Medicine for Myeloid Malignancies with 5-Azacitidine
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain significant clinical challenges, with only a fraction of patients achieving long-term survival. The most commonly used therapy in North America is 5- azacitidine (5-aza), and while 5-aza benefits some patients, 40% of treated patients have no response. It is not understood why patients become resistant to 5-aza and so, given the importance of 5-aza in MDS/AML therapy, it is important to understand the mechanisms of 5-aza resistance. The goal of this project is to understand both why patients are resistant to 5-aza, and to provide insights to develop future novel therapies.
Myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML) remain significant clinical challenges, with only a fraction of patients achieving long-term survival. The most commonly used therapy in North America is 5- azacitidine (5-aza), and while 5-aza benefits some patients, 40% of treated patients have no response. It is not understood why patients become resistant to 5-aza and so, given the importance of 5-aza in MDS/AML therapy, it is important to understand the mechanisms of 5-aza resistance. The goal of this project is to understand both why patients are resistant to 5-aza, and to provide insights to develop future novel therapies.
VancouverBC
Canada
Career Development Program – Special Fellow Grant
In partnership with our American affiliate, Leukemia and Lymphoma Society (US), we offer career development awards to postdoctoral fellows and instructors, as well as early-career independent investigators, engaging in basic, translational, or clinical research to help understand and treat hematologic malignancies and relevant premalignant conditions.
Dr. Elvin Wagenblast
University Health Network
Modeling the initiation and progression of Down Syndrome-associated leukemia using CRISPR/Cas9 at single cell resolution
Leukemia is the most common cancer in children, accounting for almost 1 out of 3 cancers. It is even more prevalent in children with Down syndrome, a chromosomal abnormality caused by a third copy of chromosome 21. In particular, children with Down syndrome have a 150-fold increased risk of developing acute myeloid leukemia during the first years of their childhood. In 30% of newborns with Down syndrome a transient pre-leukemia disease occurs. During this pre-leukemia phase, immature white blood cells called megakaryoblasts divide uncontrollably and can cause damage to several tissues, but in most patients it resolves spontaneously. However, in 20% of these cases, the pre-leukemic disease later returns and progresses into full acute myeloid leukemia. The overall aim of the proposal is to understand why an extra copy of chromosome 21 predisposes Down syndrome children to leukemia and to understand the mechanism of leukemia initiation and progression. Dr. Wagenblast’s long-term vision is to prevent the progression of pre-leukemia to acute myeloid leukemia by specifically removing the pre-leukemic cells. This could serve as a general prevention strategy in Down syndrome children diagnosed with pre-leukemia.
Leukemia is the most common cancer in children, accounting for almost 1 out of 3 cancers. It is even more prevalent in children with Down syndrome, a chromosomal abnormality caused by a third copy of chromosome 21. In particular, children with Down syndrome have a 150-fold increased risk of developing acute myeloid leukemia during the first years of their childhood. In 30% of newborns with Down syndrome a transient pre-leukemia disease occurs. During this pre-leukemia phase, immature white blood cells called megakaryoblasts divide uncontrollably and can cause damage to several tissues, but in most patients it resolves spontaneously. However, in 20% of these cases, the pre-leukemic disease later returns and progresses into full acute myeloid leukemia. The overall aim of the proposal is to understand why an extra copy of chromosome 21 predisposes Down syndrome children to leukemia and to understand the mechanism of leukemia initiation and progression. Dr. Wagenblast’s long-term vision is to prevent the progression of pre-leukemia to acute myeloid leukemia by specifically removing the pre-leukemic cells. This could serve as a general prevention strategy in Down syndrome children diagnosed with pre-leukemia.
TorontoON
Canada
Spark Grant – Novel Technology Application in Cancer Prevention and Early Detection
In partnership with the Canadian Cancer Society (CCS), we are funding an exciting research project through the Novel Technology Application in Cancer Prevention and Early Detection program. The intent of the program is to “spark” and accelerate new activity in the development and/or application of truly novel approaches to cancer prevention and early detection.
Dr. Maja Krajinovic
CHU Sainte-Justine Research Centre
MicroDNA signature for prognosis of childhood acute lymphoblastic leukemia
Acute lymphoblastic leukemia (ALL) is the most common type of childhood blood cancer. Relapsed and treatment-resistant ALL poses significant challenges in terms of clinical management. Being able to diagnose new and relapsed cases of ALL earlier would allow people to receive treatments as soon as possible, improving the likelihood of success. To achieve this, Dr Krajinovic and her team are testing whether small circular pieces of DNA are effective markers of disease. DNA is usually linear but the recent discovery of these circular pieces of DNA point to their potential as stable and easily detectable markers of cancer. The researchers are trying to identify a circular DNA signature and optimize an analysis technique that would allow them to detect these markers in a fast and cost-effective way. If successful, this approach could radically change how children with ALL are cared for, helping them live longer.
Acute lymphoblastic leukemia (ALL) is the most common type of childhood blood cancer. Relapsed and treatment-resistant ALL poses significant challenges in terms of clinical management. Being able to diagnose new and relapsed cases of ALL earlier would allow people to receive treatments as soon as possible, improving the likelihood of success. To achieve this, Dr Krajinovic and her team are testing whether small circular pieces of DNA are effective markers of disease. DNA is usually linear but the recent discovery of these circular pieces of DNA point to their potential as stable and easily detectable markers of cancer. The researchers are trying to identify a circular DNA signature and optimize an analysis technique that would allow them to detect these markers in a fast and cost-effective way. If successful, this approach could radically change how children with ALL are cared for, helping them live longer.
MontrealQC
Canada
Translation Research Program
In partnership with our American affiliate, Leukemia & Lymphoma Society (US), we provide funding for Translational Research Program (TRP) grants awarded to Canadian researchers. The Translational Research Program (TRP) puts you on the bench-to-bedside fast track when it comes to finding better treatment and cures for blood cancers. Through this program, we are funding new and innovative research that shows high promise for translating basic biomedical knowledge to clinical application.
Dr. Katherine Borden
IRIC - Institute for Research in Immunology and Cancer
The oncogene eIF4E coordinates extracellular signalling in AML
Relative to normal cells, cancer cells are often characterized by substantial changes to their surface in order to mediate their oncogenic properties. Factors on these surfaces can include multidrug resistance transporters which pump drugs out of the cell, enzymes that are involved in breaking down the surrounding tissue to enable cancer cells to migrate and invade other parts of the body, as well as features that help the cells survive in the tumour microenviroment. In this way, changes to the cell surface architecture can lead to dramatic alterations in how cells respond to growth signals, drugs and affect their mobility. We identified the oncoprotein, eIF4E, as a factor that could substantially alter the cell surface and identified this ability as critical for its cancer causing properties. eIF4E is elevated in acute myeloid leukemia (AML), lymphomas and other hematological malignancies. We will examine how eIF4E could impact the tumour microenvironment and demonstrate that eIF4E could alter cells through cell-extrinsic means i.e. control the tumour microenvironment “remotely”.
Relative to normal cells, cancer cells are often characterized by substantial changes to their surface in order to mediate their oncogenic properties. Factors on these surfaces can include multidrug resistance transporters which pump drugs out of the cell, enzymes that are involved in breaking down the surrounding tissue to enable cancer cells to migrate and invade other parts of the body, as well as features that help the cells survive in the tumour microenviroment. In this way, changes to the cell surface architecture can lead to dramatic alterations in how cells respond to growth signals, drugs and affect their mobility. We identified the oncoprotein, eIF4E, as a factor that could substantially alter the cell surface and identified this ability as critical for its cancer causing properties. eIF4E is elevated in acute myeloid leukemia (AML), lymphomas and other hematological malignancies. We will examine how eIF4E could impact the tumour microenvironment and demonstrate that eIF4E could alter cells through cell-extrinsic means i.e. control the tumour microenvironment “remotely”.
MontrealQC
Canada
Dr. Aaron Schimmer
University Health Network
The Beer Store Special Recognition Award Recipient 2019
Targeting the ubiquitin E1 ligase, UBA1, in AML
TAK-243 is a new drug that blocks the cell’s garbage disposal system. We have shown that TAK-243 kills AML cells in culture and mouse models while sparing normal cells. Based on these data, we propose a clinical trial of TAK-243 in patients with refractory AML. In support of this clinical trial, we will develop a laboratory-based test to determine whether TAK-243 can bind and inhibit its target. We will also investigate mechanisms by which cells become resistant to TAK-243. Finally, we will test new drug combinations that could enhance the ability of TAK-243 to kill AML cells while continuing to spare normal cells.
Targeting the ubiquitin E1 ligase, UBA1, in AML
TAK-243 is a new drug that blocks the cell’s garbage disposal system. We have shown that TAK-243 kills AML cells in culture and mouse models while sparing normal cells. Based on these data, we propose a clinical trial of TAK-243 in patients with refractory AML. In support of this clinical trial, we will develop a laboratory-based test to determine whether TAK-243 can bind and inhibit its target. We will also investigate mechanisms by which cells become resistant to TAK-243. Finally, we will test new drug combinations that could enhance the ability of TAK-243 to kill AML cells while continuing to spare normal cells.
Toronto
Canada
Dr. Robert Kridel
Princess Margaret Cancer Center, University Health Network
Delineation of the molecular heterogeneity underlying treatment failure in follicular lymphoma
Follicular lymphoma is the 2nd most common lymphoma type diagnosed in the US. Despite recent advances, follicular lymphoma remains largely incurable and the vast majority of patients experience progression. Some patients may remain free of disease for 10 years or longer following initial treatment and have a favorable outlook, while others may experience early disease progression and are at risk of dying prematurely from lymphoma. Thus, despite all follicular lymphoma patients being diagnosed with the same lymphoma type, their outcomes are extremely variable. An increasing number of treatment options are becoming available, but we are currently unable to tailor treatment to each individual patient’s lymphoma, for two reasons: 1) we are unable to accurately predict risk of progression before starting treatment; 2) we do not understand what patients would benefit more from one treatment compared to another. Herein, we propose to solve these two deficiencies in order to improve outcomes for follicular lymphoma patients via enhanced precision diagnostics of tumor genetics that will lead to more individualized therapy.
Follicular lymphoma is the 2nd most common lymphoma type diagnosed in the US. Despite recent advances, follicular lymphoma remains largely incurable and the vast majority of patients experience progression. Some patients may remain free of disease for 10 years or longer following initial treatment and have a favorable outlook, while others may experience early disease progression and are at risk of dying prematurely from lymphoma. Thus, despite all follicular lymphoma patients being diagnosed with the same lymphoma type, their outcomes are extremely variable. An increasing number of treatment options are becoming available, but we are currently unable to tailor treatment to each individual patient’s lymphoma, for two reasons: 1) we are unable to accurately predict risk of progression before starting treatment; 2) we do not understand what patients would benefit more from one treatment compared to another. Herein, we propose to solve these two deficiencies in order to improve outcomes for follicular lymphoma patients via enhanced precision diagnostics of tumor genetics that will lead to more individualized therapy.
TorontoON
Canada
Specialized Centre of Research (SCOR) Grant Program
In partnership with our affiliate, Leukemia & Lymphoma Society (US), we are providing funding to research that is intended to bring together established investigators from one or several institutions to develop a focused research program, foster new interactions and cooperation, and enhance interdisciplinary research among the participants. The overall goal of this mechanism is to enhance the development of innovative strategies for the treatment, diagnosis or prevention of hematological malignancies. Strategies that move discoveries from the bench to the clinic are of high importance as are integrated translational projects.
Dr. Tak Mak
University Health Network
Therapeutic implications of altered epigenetics and DNA damage responses in hematologic disorders
Acute myeloid leukemia and peripheral T-cell lymphoma are diseases with poor prognosis and limited treatment options. Mutations in three genes (TET2, DNMT3A and IDH) with similar functions contribute to the development of both of these diseases, but how they do so is unclear. New therapies targeting the effects of these mutations are being developed, but even the most promising of these are likely to be effective in only a subset of patients. A better understanding of how these mutations contribute to leukemia and lymphoma, and how they affect treatment resistance will lead to new and better therapies. Dr. Mak and his team are examining DNA and proteins of individual cells in order to identify how these mutations cause disease and resistance to therapy.
Acute myeloid leukemia and peripheral T-cell lymphoma are diseases with poor prognosis and limited treatment options. Mutations in three genes (TET2, DNMT3A and IDH) with similar functions contribute to the development of both of these diseases, but how they do so is unclear. New therapies targeting the effects of these mutations are being developed, but even the most promising of these are likely to be effective in only a subset of patients. A better understanding of how these mutations contribute to leukemia and lymphoma, and how they affect treatment resistance will lead to new and better therapies. Dr. Mak and his team are examining DNA and proteins of individual cells in order to identify how these mutations cause disease and resistance to therapy.
TorontoON
Canada
For research projects funded prior to 2021, please contact us.