Scientists have uncovered ways to turn the body’s natural immune system against cancer – an approach termed immunotherapy. While highly effective for some patients and cancer types, many patients do not respond. This creates a fundamental knowledge gap: why do only certain patients respond to immunotherapies? The answer may lie in the adage – “you are what you eat”. Cancers, at the cellular level, consume lots of fats, sugars, and 1000’s of other molecules collectively termed ‘the metabolome’. This leads to immune cells needing to fight for key fuels, and tumor cell production of toxic by-products which can kill natural immune cells. Together, this can incapacitate the immune system and may be why immunotherapies fail. Resolving this metabolic hurdle will require emerging, state-of-the-art technologies that can distinguish cancer cell metabolism and immune cell metabolism as they exist in the tissue (i.e. with their spatial distribution preserved). This project aims to develop and apply cutting-edge technologies to profile tumors which are responsive & unresponsive to immunotherapy, providing a fundamental understanding of tumor metabolism and allowing us to identify new opportunities to improve targeted immunotherapy treatments.
Research Pillar: Biomedical Research
AI-based Platform for Ovarian Cancer Biomarker Discovery and Refinement
Ovarian cancer ranks fifth in cancer deaths among women. The revolution in our understanding of genetic and molecular drivers of other cancers has resulted in major improvements in how such cancers are routinely managed. However, standard clinical management of ovarian cancer have not seen any improvements. Significant clinical implications have been achieved by the classification of ovarian cancer based on genetic markers. Pathologists achieve a cornerstone in cancer diagnosis and prognostication by studying the visual microscopic study of diseased tissue (histology). Histology reveals wealth visual information of disease biology about the aggregation effect of genetic alterations on cancer cells. In this project, we plan to produce automated AI-based differential diagnostic tool for major ovarian cancer subtypes, and moreover, investigate the relationship between genetic markers, histology and disease outcome. We then combine these kinds of data for a comprehensive profile of each tumor. New knowledge generated from this project will shed light on the link between histology and genetic markers and identify potential biomarkers that can be rapidly and accurately tested to stratify ovarian cancer for accurate treatment selection.
Use of CAR Tregs to induce transplantation tolerance
Organ transplantation, the primary treatment for organ failure, necessitates lifelong immunosuppressive therapy. Traditional immunosuppressants like steroids pose risks of severe infections and cancer due to their non-specific action. To address this, we’ve developed engineered Tregs, which migrate specifically to transplanted organs and prevent rejection. Initial studies in mice demonstrate promising delay in skin graft rejection. However, the effectiveness of Tregs combined with various immunosuppressive drugs used in transplantation remains unclear. My research aims to bridge this gap by investigating how engineered Tregs interact with common drugs to identify optimal combination therapies for transplant tolerance induction. I will also explore the underlying mechanisms of immune suppression. Ultimately, this work will inform the design of clinical trials, optimizing drug-Treg combinations as a therapeutic approach to combat transplant rejection.
Risk factors for cognitive impairment and substance-induced psychosis in people living in precarious housing or homelessness.
Social marginalization is a risk factor for poor health and is associated with psychotic and substance use disorders, traumatic brain injury (TBI), HIV and hepatitis C infection. Substance use and brain insults, such as TBIs, can lead to changes in brain function, yet we do not fully understand how they contribute to cognitive impairment (possibly due to accelerated aging) and other symptoms like psychosis. This study aims to assess the extent to which individuals with brain insults using substances are at risk of cognitive impairment or psychosis, and if using antipsychotics can affect these symptoms. This study will use data from the Hotel Study, an ongoing longitudinal community-based study aimed at characterizing factors affecting health of marginalized individuals based in Vancouver’s Downtown Eastside. Participants completed comprehensive assessments at study entry and monthly evaluations of prescription and non-prescription substance use, symptoms of psychosis, and annual cognitive assessments including brain imaging. Statistical modelling will be used to address objectives. We anticipate that our results will help better guide clinicians in engaging and treating this vulnerable population to prevent chronic disability.
Investigating oncogenic mechanisms in DICER1 syndrome-associated ovarian Sertoli-Leydig cell tumors
DICER1 syndrome is a rare, inherited disorder; individuals with a mutation (change) in the DICER1 gene are at increased risk of a variety of cancerous and non-cancerous (benign) tumors. It affects mostly children and young adults. These cancers can be lethal at advanced stages of disease with no biologically-informed treatment strategies available. Despite the discovery of the gene, DICER1, being attributed to cancer development, the translation of this genomic discovery to the bedside to improve cancer care has been hindered by the lack of relevant models to study the disease. My post-doctoral research project will focus on one such aggressive rare cancer, called ovarian Sertoli-Leydig cell tumor. I will use the unique tools/resources such as a large cohort of patient samples and the first-ever mouse model of DICER1 syndrome-associated cancer to understand the biology of this rare ovarian cancer and identify potential druggable candidates for future therapeutic development.
Engineering Transfusable Platelets for Improved Hemorrhage Control
Failure to control bleeding, such as during trauma and childbirth, accounts for more than half of all operating room deaths. Platelets are blood cells that stick to sites of active bleeding and release proteins to initiate blood clotting. The gold standard therapy for treating severe bleeds is transfusing the patient with more platelets. However, in some cases, transfused platelets can have impaired clotting, thus increasing mortality. A strategy to improve platelet function is to load platelets with more clot-initiating proteins. We have previously shown that platelets can be engineered to express new proteins using mRNA-lipid nanoparticles (mRNA-LNP). This project will expand on these findings and use mRNA-LNP to deliver the genetic blueprint for clot-initiating proteins into platelets to enable the production of clotting factors that will prime the platelets for improved clotting. The research will be in active collaboration with academic and industrial partners to facilitate the development of a clinical product from any generated intellectual property. Enhancing the natural properties of platelets will improve options for bleeding control, with the potential to reduce the incidence of hemorrhage-related deaths in Canada.
Elucidating how the Sotos Syndrome gene NSD1 controls gene expression during neuronal differentiation.
Each cell has the same genetic information, our DNA. Yet, our body consists of many different cell types (eg. muscle cells, brain cells, etc). To become a specific cell type, our cells have the ability to turn genes in our DNA on or off. This selective control of genes is achieved via “epigenetics”, which means on top (epi-) of our genes (genetics). Epigenetics involves chemical changes to proteins that organize our DNA, which are called histones. Changes to histones are made by epigenetic enzymes. When epigenetic enzymes are defective the wrong changes are made to histones. In turn, the wrong genes are turned on or off, leading to disease. An example of such a disease is Sotos Syndrome, a neurodevelopmental disorder caused by a defect in the epigenetic enzyme NSD1. Exactly how defective NSD1 leads to misguided control of genes is unknown. To examine this, I will use gene editing and delete NSD1 in neuronal precursor cells. Next, I will study the effect of defective NSD1 on histone changes and identify which genes are wrongfully turned on or off in these cells. The results from this study will show how defective NSD1 leads to misguided gene control and can help identify new options for the treatment of Sotos Syndrome.
A chemical biology approach to uncovering modulators of a Parkinson’s disease-linked protein
Enzymes are biological machines which facilitate crucial processes in the human body. A reduction in the function of a given enzyme, sometimes brought about by an alteration or “mutation” to the underlying genetic code, often results in disease. In Parkinson’s disease (PD), a mutation in the GBA1 gene can cause earlier disease onset and rapid motor decline. Furthermore, the enzyme glucocerebrosidase (GCase) that is encoded by GBA1 is less active in PD patients regardless of whether they have a defective GBA1 gene. We hypothesize that GCase is altered or “modulated” by other proteins within the cell. My first goal in this project will be to create improved ways to measure the activity of GCase in live human cells. Previous work has shown that “ratiometric fluorescence sensors” – small molecules which light up when processed by a target enzyme – have high efficacy towards this end. The activity of a large library of existing drug candidates will then be tested for their ability to modulate GCase. Changes measured in GCase activity within cells treated with these drug candidates will help identify these aforementioned unknown “modulators”, thus revealing new insights into the mechanisms of PD and opening new therapeutic approaches.
Using unbiased whole brain methods to understand how impact direction affects the neuropathology of traumatic brain injury in mice
Traumatic Brain Injury (TBI) is a leading cause of death and disability worldwide and often caused by falls, motor vehicle accidents, sports, and violence. Most TBIs are mild (concussion-like) and involve head motion in one or more planes. Although many clinical studies show that complex rotational head motion is associated with worse outcomes, the underlying reasons are unknown. My project aims to fill this gap by determining how head motion during impact relates to changes in levels of injury blood biomarkers and brain pathology in mice. Using our established non-surgical TBI model called CHIMERA (to imitate human TBI), I will deliver impact to the back or side of the head, and measure how the head moves during these impacts using high-speed cameras. I will use cutting edge tissue clearing method to examine brain in 3D and map changes in neuronal activity, axonal and vascular integrity. I will test how these impacts lead to changes in blood biomarkers using clinically relevant tests. Overall, this study will help us understand how impact biomechanics relates to TBI outcomes, which is tremendously important for the future design of helmets and other safety equipment, sport coaching, and concussion rehabilitation.
Development of mutation-robust vaccines and antibodies, and their implications for the evolution of SARS-CoV-2
COVID-19 has caused over 774 million cases and 7.02 million deaths worldwide as of February, 2024. The causative RNA virus, SARS-CoV-2, has the ability to rapidly mutate genetically, and these mutations allow it to swiftly infect with increased efficacy and/or severity. These mutations are of concern because they allow SARS-CoV-2 to evade not only antibodies formed by natural infection or vaccines, but also recombinant antibody therapeutics. With new variants emerging roughly every other month, it will not be long before the current repertoire of antibodies and vaccines against SARS-CoV-2 becomes obsolete. Although it is difficult to predict the mutations in the next variant, it is possible with current technologies to examine potential mutations and the activity of such mutated variants. In this proposal, we will test the robustness of mutation-tolerant de novo vaccines and antibodies against SARS-CoV-2. We also seek to understand how SARS-CoV-2 evolves over time and to decipher the mechanism of antigenic escape from diverse antibodies. This platform can guide us in the design of better therapeutics to combat current and future variants of SARS-CoV-2, and other viruses.