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2024 Grant Recipients
Dr. Steven Chan
Dr. Chan is a Senior Scientist and Staff Physician at Princess Margaret Cancer Centre and an Assistant Professor in the Department of Medicine at the University of Toronto. He completed his medical training, residency and Fellowship at Stanford University and Stanford Hospitals. Dr. Chen also has a PhD in Immunology from Stanford University. His current research focuses on developing new treatment approaches against blood cancer.
Investigating CD59 as a Novel Therapeutic Target Against TP53-Mutated Acute Myeloid Leukemia
Principal Investigator: Dr. Steven Chan (Senior Scientist)
Acute myeloid leukemia (AML) is a blood cancer that kills over 1,000 Canadians each year. The prognosis of AML patients is highly variable, depending on the specific genetic changes found in the patients’ leukemia cells. Specifically, one subtype of AML with mutations in a gene called TP53 is associated with a poor prognosis and current treatments are ineffective for this AML subtype.
Dr. Chan and his team recently discovered that high expression of another gene called CD59 is associated with the TP53 mutation in AML. Importantly, they found that decreasing the level of CD59 drastically reduces the growth and survival of TP53-mutated AML cells in a petri dish.
The team is planning to determine if the impact of decreasing CD59 expression in AML cells can also be observed in pre-clinical models. This is critical as findings made in a petri dish do not always represent what happens in a living organism. They will also investigate whether they can use a modified form of the protein called intermedilysin to specifically degrade CD59 and ultimately slow down the growth of TP53-mutated AML cells. The Potential Impact If successful, the tested protein could be turned into a new drug to treat TP53-mutated AML and ultimately improve the survival of patients with this deadly disease.
Dr. Housheng Hansen He
Dr. He is a Senior Scientist at Princess Margaret Cancer Centre and a Professor in the Department of Medical Biophysics at the University of Toronto. His research focuses on cancer epigenetics and RNA therapy. He has published over 100 research articles. Dr. He leads the RNA Nanomedicine Initiative and RNA Nanomedicine Core at The Princess Margaret and holds a Tier 1 Canada Research Chair in RNA Medicine.
Tumour-Selective Induction of Immunogenic Cell Death via Organ-Tropic Delivery of Switchable mRNA for Non-Small Cell Lung Cancer Immunotherapy
Principal Investigator: Dr. Housheng Hansen He (Senior Scientist)
Co-Applicant: Dr. Bowen Li
Cancer immunotherapy, which harnesses the power of the patient’s own immune system, has revolutionized treatment for many cancers. Despite their effectiveness, these treatments can lead to significant side effects as they can cause the immune system to not only attack cancer cells but also healthy cells and tissues.
Dr. He and his team are designing messenger RNAs (mRNAs) to carry specific instructions to cancer cells, like sending a message only cancer cells can read. The instructions will cause cancer cells to produce ‘toxic’ proteins, which may directly cause the cancer cells to self-destruct or make the cancer cells more visible and vulnerable to the body’s immune system.
To ensure that the mRNAs only target cancer cells, Dr. He’s team is incorporating so-called RNA switches into the mRNA. RNA switches act like light switches that only work in the presence of certain conditions found in cancer cells. When the switch is ‘on’, it allows the production of the ‘toxic’ proteins. In healthy cells, where the conditions are absent, the switch remains ‘off’, keeping the healthy cells safe. Then, to directly deliver the mRNA where it is needed, the team is using lipid (fat) nanoparticles, which have a natural tendency to accumulate in certain organs. The team is exploring RNA switches and lipid nanoparticles in the lung.
The combined approach of RNA switches and nanoparticles will ensure that the treatment is concentrated where it is most needed and, contrary to current systemic treatments, limit toxicity to healthy tissues. If successful, this approach could revolutionize cancer treatment and provide a promising alternative to conventional immunotherapy.
Dr. Thomas Purdie
Dr. Purdie is a Clinician Scientist and Staff Medical Physicist at Princess Margaret Cancer Centre and an Associate Professor in the Departments of Radiation Oncology and Medical Biophysics at the University of Toronto. He has been developing machine learning for radiation oncology since 2012 and has patented and commercialized machine learning technologies for automating clinical radiation oncology processes.
Machine Learning Generated Imaging to Close the Gap Between Diagnosis and Radiation Treatment Delivery
Principal Investigator: Dr. Thomas Purdie (Senior Scientist)
Radiation therapy (RT) is an essential cancer treatment that benefits approximately half of all patients diagnosed with cancer. The RT treatment process currently requires additional imaging of the patient to create the patient’s RT treatment. Unfortunately, standard-of-care diagnostic imaging is not suitable for creating RT treatments as it uses different imaging parameters, accessories and patient positioning. The need for additional RT imaging can delay treatment, which has been correlated with worse patient outcomes.
Dr. Purdie and his team have previously developed, patented and clinically deployed artificial intelligence (AI) technology to automate the complex and time-consuming task of creating patient-specific RT treatments for hundreds of patients at The Princess Margaret, improving the efficiency of the RT treatment process by 60% (71 hours per patient). The team has also developed AI technology that accurately generates RT imaging of the patient from readily available standard-of-care diagnostic imaging.
The team will explore integrating their AI technologies to establish a new clinical RT treatment process that creates RT treatments directly from diagnostic imaging without requiring additional RT imaging.
By collapsing the time between diagnosis and RT treatment, the team aims to better utilize limited clinical resources and overcome clinical redundancies, improve patient care by reducing the wait time for RT treatment, reduce hospital visits for the patient, and improve the quality and outcomes of RT treatment.
2023 Grant Recipients
Dr. Cheryl Arrowsmith
Cheryl Arrowsmith is a Senior Scientist at the Princess Margaret Cancer Centre, Professor in the Department of Medical Biophysics and Chief Scientist of the Structural Genomics Consortium (SGC) at the University of Toronto. Her research focuses on new drug discovery strategies for cancer. She has published over 300 research articles, and was recognized by Clarivate Analytics as being among the worlds top 1 % of highly cited scientists in 2018, 2019 and 2022, is a AAAS Fellow and a Fellow of the Royal Society of Canada, and was co-founder of Affinium Pharmaceuticals.
A novel Targeted Protein Degradation (TPD) strategy to evaluate the role and therapeutic potential of NSD2 in leukemia
Principal Investigator: Dr. Cheryl Arrowsmith (Senior Scientist)
Collaborators: Dr. Mark Minden and Dr. Mathieu Lupien
Acute lymphoblastic leukemia (ALL) remains a challenging cancer to treat and is one of the deadliest leukemias in children. In ALL, therapeutic resistance has been causally linked to mutations in the DNA that makes a protein (a complex molecule that carries out functions in a cell) called NSD2. The NSD2 protein interacts with DNA and other proteins, playing a critical role in regulating the genes that drive cancer cell survival and spread to other parts of the body, especially the brain. Normally, the cell's natural "waste disposal system" helps get rid of these proteins to regulate their numbers, destroy damaged or faulty ones and make room for new, functioning proteins. But mutated NSD2 puts the growth of cancer cells intro overdrive and avoids getting destroyed by the cell's natural "waste disposal system."
Senior Scientist Dr. Cheryl Arrowsmith and team, along with collaborators Drs. Mark Minden and Mathieu Lupien, have developed a new, drug-like chemical that causes the NSD2 protein to be degraded (destroyed) through the cell's natural "waste disposal system." This new treatment approach of targeting protein degradation can potentially kill cancer cells that depend on NSD2 to survive, grow and spread to the brain. The team will explore how NSD2 fuels cancer cell survival and spreading to the brain, and if NSD2 degradation can prevent these outcomes.
Dr. Naoto Hirano
Naoto Hirano is Senior Scientist at Princess Margaret and Professor of Immunology at University of Toronto. Hirano’s lab is interested in T cell-based cancer immunotherapy and has developed new CAR and T cell receptor gene therapies, which have been licensed to industrial partners for clinical translation and commercialization.
Development of bi-specific T cell engagers (BiTEs) for the treatment of acute myeloid leukemia (AML)
Principal Investigator: Dr. Naoto Hirano (Senior Scientist)
Co-Applicant: Dr. Mark Minden
Acute myeloid leukemia (AML) is a blood cancer with low rates of survival and few treatment options beyond chemotherapy. Though chemotherapy can slow AML progression, disease relapse often occurs due to the development of chemo-resistant leukemic cells. New therapies are clearly needed.
Bispecific T cell engagers (BiTEs) are an exciting new form of immunotherapy that uses antibodies to redirect a patient’s T cells to kill cancer cells. Unlike other forms of immunotherapies, BiTEs do not require the genetic manipulation of a patient’s cells. So, BiTEs can be given to a broader population of patients. Approved by Health Canada in 2016, BiTe therapies have shown impressive clinical responses in patients with acute lymphocytic leukemia (ALL). However, there are currently no BiTE therapies for AML, mainly due to difficulties developing AML-specific antibodies that do not impact healthy tissue.
Recently, Dr. Naoto Hirano and his team developed a first-in-class antibody that targets a fragment of the Wilms tumour 1 (WT1) protein found on leukemia cells, but rarely on normal blood stem cells. Cross-testing confirmed that the antibody is effective in killing cancer cells and safe on normal blood stem cells (manuscript in preparation, patent pending).
Using this antibody and available resources, this study seeks to develop a BiTE targeting the WT1 protein, to lay the groundwork for a new BiTE therapy to treat patients with AML.
Dr. Mohammad
Mazhab-Jafari
Dr. Mohammad Mazhab-Jafari is a Scientist at the Princess Margaret Cancer Centre, and Assistant Professor in the Department of Medical Biophysics at the University of Toronto. He received his BSc and MSc from McMaster University in 2004 and 2006, respectively, specializing in genetic engineering and nuclear magnetic resonance (NMR) spectroscopy. He then obtained his PhD at the University of Toronto studying switchable proteins (i.e., GTPases) using NMR and X-ray crystallography.
Targeting de novo synthesis of fatty acids in cancer cells
Principal Investigator: Dr. Mohammad Mazhab-Jafari (Scientist)
Fatty acid synthesis is a process in the cell that creates fatty acids, which have many functions in our body, including energy for our tissues and cells as well as energy storage. This process is overactive in cancer. Fatty acid synthesis is initiated by a chemical reaction caused by an enzyme (a type of protein or molecule that helps carry out chemical reactions in the cell) called FASN. This enzyme is responsible for various important roles in the body, but cancer cells also take advantage of its power.
An elevated level of FASN is a hallmark of cancer, involved in how the cancer starts, making it an ideal target for therapy. Elevated levels of FASN are also associated with chemotherapy resistance, early recurrence and poor prognosis. Many drugs have been developed to block the activity of FASN, but only one has reached clinical trials – an anti-cancer drug called Denifanstat. This is mainly because the other FASN-blocking drugs caused too many side effects.
Dr. Mohammad Mazhab-Jafari and team aim to fully understand how FASN works at the atomic level, which has never been done before. So far, the team has successfully determined the structure of FASN, and plans to “trap” FASN to observe how it interacts with other substances and proteins. By better understanding the structure of FASN and how different parts interact with the environment around it, the team can design new and better FASN-blocking drugs to treat cancer more effectively.
2022 Grant Recipients
Dr. Eric Lechman
Affiliate Scientist,
Princess Margaret Cancer Centre
Investigating Ciliopathy as a Predisposition for Pediatric Leukemia
Down syndrome is caused by the presence of an extra chromosome – chromosome 21. Children with Down syndrome also have a 150-fold increased risk of developing preleukemia that can evolve into leukemia. Dr. Lechman was involved in a landmark study in 2021 that demonstrated that pre-leukemia in Down syndrome arises only within rare hematopoietic stem cells (HSC). What remains unclear is how an extra copy of chromosome 21 predisposes HSC toward leukemia.Preliminary data from Dr. Lechman suggests that Down syndrome-related HSC express a gene signature consistent with dysfunctional primary cilia – a previously unexplored connection. The primary cilium is a solitary, hair-like appendage required for cells to respond appropriately to their environment. In the context of Down syndrome, it’s possible that the hair on the blood cells becomes abnormal, which in turn misinterprets environmental cues and leads to leukemia.
Dr. Lechman and his team plan to study approximately 60,000, single blood progenitor cells with state-of-the-art DNA structure, RNA and Protein analyses. This will create the first high resolution dataset revealing differences between Down syndrome and normal blood cells.
The proposal has the potential to understand how chromosome 21 influences leukemia initiation in children with Down syndrome. More broadly, the mechanisms it uncovers may also reveal the genetic alterations that cause leukemia in adults as well. That’s because it will shed light on the little-understood cellular origins that initiate leukemia and possibly govern the properties of the resultant disease.
Dr. Natasha Leighl
Medical Oncologist,
Princess Margaret Cancer Centre
Accelerating Lung Cancer Diagnosis
Lung cancer remains the deadliest cancer in Canada, accounting for 25% of all cancer deaths. For advanced non-small cell lung cancer (NSCLC) patients, survival is directly impacted by the time from symptom onset and diagnosis to the start of treatment. Unfortunately, the cancer journey for advanced NSCLC patients is often drawn out. In the era of precision medicine, molecular testing of tumour tissue with a biopsy is the gold standard for directing treatment decisions for advanced NSCLC patients. However, 15-40% of patients do not have enough tissue for successful molecular testing, and delays obtaining tumour tissue and molecular results mean most patients do not have results when they see their oncologist. These days, such time lags are further exacerbated by the COVID-19 pandemic, causing immense stress for patients and costing precious time for oncologists to implement effective therapy.To drastically reduce the time delay before treatment, Dr. Leighl would like to trial a new technology: liquid biopsies. Liquid biopsies are non-invasive blood tests that detect circulating tumour DNA (ctDNA), biology markers that indicate cancer in the blood. Molecular information from liquid biopsies can help diagnose and discover molecular targets much faster than standard tumour tissue biopsy testing. Liquid biopsies are also more convenient and safer than tumour biopsies for patients, and can result in cost savings.
Dr. Leighl has designed a study to use liquid biopsy for advanced NSCLC patients. The tests will be implemented at the time of diagnosis to determine what biological markers the liquid biopsies detect, and to see how they can be used to accelerate time to treatment. While the technology is still new, Dr. Leighl and her team believe they will see meaningful results that might point to a new gold standard when it comes to diagnostics.
It is anticipated that this approach will significantly reduce wait times between diagnosis and treatment for advanced NSCLC patients. Accelerating molecular diagnosis and time to treatment will have important implications for survival, symptom control and quality of life, ensuring the best possible outcomes for those afflicted with lung cancer.
Dr. Shane Harding
Scientist,
Princess Margaret Cancer Centre
Dynamic heterogeneity of the prostate microenvironment in patients undergoing external beam radiotherapy
Radiotherapy is used to treat half of all cancer patients but fails if the cancer has spread throughout the body. In some patients, adding immunotherapy to their radiotherapy has led to dramatic cures. Unfortunately, this combination treatment does not work in all patients for reasons that we do not fully understand. One major gap in our knowledge is that we do not actually know how cells in patients respond to radiotherapy at the molecular level, despite the fact that radiotherapy has been used in treatment for decades.
Dr. Harding is assembling a multi-disciplinary team to study radiation in the context of prostate cancer, with the hope of better understanding how cells respond to radiotherapy at the molecular level, and therefore how it can be better utilized with immunotherapy to improve survival rates. Work from the Harding Lab and many others has already shown that the molecular signals produced by cells after radiotherapy can recruit and activate the immune cells that are necessary for immunotherapy to be effective.
With this proposal, Dr. Harding and his team plan to identify a cohort of prostate cancer patients at high risk for recurrence after radiotherapy. Biopsies will be collected before and after their treatment. Using modern technologies, the team will profile thousands of individual cells. This approach allows the team to address several fundamental questions, including:
- How do different cell types that comprise a tumour respond to radiotherapy?
- How does radiotherapy change the types of cells within a tumour?
- How do cells within a tumour communicate with each other and the cells of the immune system?
Contact Us
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