Current and past funded research OLD

2022 Research Investment

2021 Research Investment

Dr. Versha Banerji
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 together 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
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.

MontrealQC
Canada

Jean-Sébastien Delisle
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

MontrealQC
Canada

Dr. Spencer Gibson
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 cells around them. 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
Dr. Aly Karsan
BC Cancer Agency
UFCW Special Recognition Award Recipient 2019

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

VancouverBC
Canada

Dr. John Kuruvilla
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.

TorontoON
Canada

Dr. Robert Kridel
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 explains 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
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.

VancouverBC
Canada

Dr. Sabine Mai
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.

WinnipegMB
Canada

Dr. Koren Mann
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.

MontrealQC
Canada

Dr. Mark Minden
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.

TorontoON
Canada

Dr. Anastasia Nijnik
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 analyzed 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
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. Amongst 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
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

TorontoON
Canada

Dr. Christian Steidl
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.
Dr. Thai-Hoa Tran
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 to identify 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
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.

TorontoON
Canada

Dr. Peter W. Zandstra
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.

VancouverBC
Canada

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 understand 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

Dr. Elvin Wagenblast
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.

TorontoON
Canada

Dr. Maja Krajinovic
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, and 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

Dr. Katherine Borden
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”.

MontrealQC
Canada

Dr. Aaron Schimmer
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.

TorontoON
Canada

Dr. Robert Kridel
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.

TorontoON
Canada

Dr. Tak Mak
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.

TorontoON
Canada

For research projects funded prior to 2021, please contact us.