Congratulations to Alberto Delaidelli, Farhia Kabeer, Kwangjin Park, Waleed Alduaij, Adi Steif, Ly Vu and Leandro Venturutti for their successful applications through the 2022 Scholar and Research Trainee competitions from Michael Smith Health Research BC.
The funding supports the advancement of world-class health research in B.C.
The Research Trainee Program supports health researchers in the training phase of their research career to enable career development and enrich BC’s health research talent.
Alberto Delaidelli: Medulloblastoma plasma membrane proteomics to inform optimal immunotherapy design
Summary: Brain cancer is the most common pediatric solid cancer, devastating the lives of more than 5,000 children and their families every year in North America. Current chemoradiotherapy approaches are often ineffective and cause serious side effects on the developing brain, such as permanent seizures and learning disabilities. Thus, more effective and less damaging therapies are urgently needed. Immunotherapy has been recently credentialed as a breakthrough in cancer therapy, with novel immunotherapy agents approved by the FDA for the treatment of childhood cancer. There is every indication that this progress presents the tip of the iceberg and that with continued efforts, effective immunotherapies can be developed for many currently incurable pediatric cancers. The ability for cancers to grow rapidly is in part due to the activation of specific proteins exposed on the membrane of cancer cells. The goal of immunotherapy is to target cells exposing these proteins while sparing normal, healthy cells; however, a major barrier is that most proteins on the surface of medulloblastoma cells are currently unknown. In this proposal we will identify optimal targets to ultimately develop immunotherapies against medulloblastoma.
Farhia Kabeer: Predictive biomarkers for ovarian cancer treatment: Analysis of patient of derived xenografts under treatment at single cell resolution
Summary: Each year in Canada, around 3,000 women will be diagnosed with high grade serous ovarian cancer (HGSOC) -- the most common type of ovarian cancer. Despite good responses to first line treatments for many women, it comes back as a resistant disease. Targeted treatments such as PARP inhibitors (PARPi) have made a big difference to HGSOC that is deficient in a DNA repair pathway (Homologous recombination repair), but this only benefits around 50 percent of women with HGSOC. PARPi combinations with drugs that target angiogenesis and the immune response remain under investigation. This project will investigate how chemotherapy vs. targeted therapies differentially affects the DNA damage and immune response in cancer and how effective non-chemotherapy combination treatments work, including different doses and schedules. Also, which patient might benefit from which treatment and when for example should the targeted therapies be given before or after the chemotherapy? Creating models similar to humans, we will transplant patient tumors (removed at surgery) on the skin and inside the abdomen of mice and analyze the molecular nature (at single cell level) of these tumors before/after treatment. Results of these studies will inform future clinical trials.
Kwangjin Park: Roles of the Lysine Methyl Transferase (KMT) 2d in hepatocyte identity and hepatocellular carcinoma progression
Summary: Liver cancer is the third most common cause of cancer-related deaths globally, and patients with liver cancer currently have limited treatment options, including tumor ablation and liver transplant. More than half of the liver cancer cases have mutations in regulators of genome structure, which play a crucial role in cellular differentiation and development by controlling gene expression patterns. Lysine Methyl Transferases 2d (KMT2d) is one of the most frequently mutated regulators. However, we do not fully understand how changes in the KMT2d can drive liver cancer. In this project, I will investigate the mechanism in which KMT2d influences liver development as well as induces liver cancer from normal liver cells using organs that mimic human livers. Moreover, discovering its interaction partners, such as transcription factors that function in turning on and off genes, will provide more comprehensive mechanistic insight into the roles of KMT2d in liver formation and health. This study will advance fundamental knowledge for future research on the liver's developmental biology and provide promising alternative therapeutic avenues for liver cancer.
Waleed Alduaij: Molecular determinants of pathogenesis and clinical outcomes in high-grade B-cell lymphoma
Summary: One-third of patients with aggressive non-Hodgkin lymphoma relapse after conventional chemotherapy and die of their disease. We need new methods to identify, at diagnosis, which patients have a high risk of relapse to improve their treatment. Genetic profiling is a powerful tool that can identify these high-risk patients. 'Double-hit lymphoma' (DHL) is one type of lymphoma that responds poorly to standard treatment. Current testing strategies cannot accurately identify all patients with DHL. We aim to improve the identification and treatment of DHL with a new test that uses a unique 'genetic blueprint'. We will apply this test on lymphoma samples from 900 aggressive lymphoma patients in British Columbia to find out its ability to identify DHL patients compared to current methods. Patients who carry this genetic blueprint may benefit from different treatment approaches that overcome the high risk of relapse. We will also conduct an in-depth genetic analysis of DHL to understand how these lymphomas develop in the body. This new knowledge will help design smarter therapies that target the tumour while sparing normal body cells. These 'targeted therapies' can avoid the significant side effects caused by intensive chemotherapy.
The Scholar Program supports early-career health researchers who are building leading-edge health research programs, training the next generation of scientists and expanding their potential to make significant contributions to their field.
Adi Steif: Single cell methods for characterizing genomic alterations in cancer
Summary: Cancer arises when a single cell acquires genetic alterations leading to uncontrolled replication. As tumour cells divide they continue to acquire genetic mutations which they pass on to their descendants, forming distinct subpopulations with different characteristics. The ability of tumours to generate genetic diversity and evolve in response to selective pressures can enable them to develop resistance to treatment. Certain forms of genetic alteration have been associated with poor patient survival in high grade serous ovarian cancer. Understanding the frequency with which these alterations arise within tumours and the diversity they generate requires profiling the genetic material of individual cancer cells. We will optimize experimental approaches for sequencing single tumour cells and develop computational and statistical methods to characterize this genetic diversity. This will provide researchers with new tools with which to study the mechanisms that underlie treatment resistance and patient relapse, and open the door for the development of new prognostic measures and therapeutic approaches.
Leandro Venturutti: Self reactivity as a driver of extranodal diffuse large B-cell lymphoma transformation and survival
Summary: Lymphoma is a form of cancer that affects immune cells called lymphocytes, a type of white blood cell. There are many subtypes of lymphocytes and lymphomas. Diffuse large B-cell lymphomas (DLBCL) develop from B lymphocytes (B-cells) and are the most common subtype of non-Hodgkin lymphoma. About one third of DLBCL extend beyond the lymph nodes ("extranodal DLBCL"), and invade vital organs such as the kidneys, lungs, and brain, with an often-fatal outcome. Our ability to predict which patients will develop extranodal DLBCL is limited, and we also lack disease-specific treatments, partly due to an incomplete understanding of how and when these tumors originate. Interestingly, recent evidence suggests extranodal DLBCL share features with autoimmune disorders -- conditions in which lymphocytes abnormally react against organs in our bodies, instead of external foes. In this study, we will investigate the relationship between the origin and progression of these diseases, in an effort to better understand how B-cells transform into cancerous cells, disseminate, and expand. Our work could help identify patients at high risk of developing extranodal DLBCL, and unveil key tumor dependencies to be leveraged as specific therapeutic targets.
Ly Vu: Post-transcriptional regulation of hematopoietic stem cell function during normal and malignant hematopoiesis
Summary: In 2016, there were approximately 22,510 Canadians living with leukemia and an estimated 2,900 Canadians died from leukemia. Acute myeloid leukemia (AML) is one of the most common types of leukemia in adults. About 30 percent of AML patients eventually relapse after treatment and suffer from very poor overall survival at this stage. It is postulated that leukemia stem cells (LSCs), a small population of leukemia cells characterized with regenerative ability, mediate resistance and relapse after therapy. My work sought to uncover the largely unknown role of the processes that control protein generation in maintaining blood stem cells and how it contributes to transformation of leukemia stem cells in cancer. This research program aims to identify new factors, which can serve as targetable molecules and pathways to specifically eliminate leukemia cells while sparing normal cells. The work will provide the scientific foundation for future developments of therapy targeting these pathways as a novel strategy in eradicating leukemia stem cells to improve outcomes in AML patients. I
In addition to the research conducted by BC Cancer-affiliated researchers, another 66 Scholars and Research Trainees across B.C. received support for their projects.