Roman M. Babicki Fellowship in Medical Research

Winner: Anne Nathalie Ruth Longakit

Nathalie is a PhD candidate in the Medical Genetics graduate program who is researching in the area of uveal melanoma, the most common cancer of the eye under Dr. Catherine Van Raamsdonk, Associate Professor, Department of Medical Genetics.

Every year, ~130 Canadians are diagnosed UM; in half of these patients, the cancer spreads to other parts of the body through a process called metastasis, after which treatment is much more difficult. Most UMs are initiated by a mutation in either the GNAQ or GNA11 gene, and almost all metastatic cases have a mutation in the BAP1 gene. Loss of BAP1 is strongly associated with worse patient outcomes and reduced survival. But, the link between BAP1 and metastasis has not been discovered. Their lab's preliminary data shows that Epithelial to Mesenchymal Transition (EMT) is a significant process in UM metastasis. EMT allows cancer cells to migrate and invade tissues by converting epithelial cells to mesenchymal cells. Variations in EMT can prevent tumor cells from completing the transition, instead, acquiring an intermediate state between the epithelial-mesenchymal (EM) spectrum. In this grey area, tumor cells are more versatile, allowing them to easily adapt to new environments, which is key to metastatic success.

The goal of Nathalie’s research is to identify subpopulations of tumor cells, which undergo EMT-like programs to understand how BAP1 mutations drive metastases to specific organ sites, by using a combination of CRISPR-Cas9 technology, single cell RNA sequencing, and epigenomic analysis. Through this work, she hopes to identify potential therapeutic targets to mitigate or prevent UM metastasis, thus improving patient outcomes.

Elie Ritch researches prostate cancer, the second leading cause of cancer death in men. In advanced cases, the cancer typically metastasizes to the bone where it is extremely invasive to profile for personalized oncology. For this reason, Elie develops bioinformatics software to profile circulating tumor DNA, small amounts of DNA from cancer cells found in the blood. Biomarkers in this DNA can inform on which therapy a patient is more likely to respond to, or to detect the cancer developing resistance to a treatment. He is currently working on developing genomic biomarkers for response to immunotherapy, and in translating this research to the clinic in a national trial for combination immunotherapy for metastatic prostate cancer.

Michael Skinnider studies cellular metabolism using mass spectrometry-based metabolomics. In order to acquire the nutrients needed to support uncontrolled growth, cancerous cells develop mutations in their DNA that change the way they break down fuels such as amino acids, sugars, and fats (called metabolites) to generate energy. By measuring hundreds of metabolites at once, metabolomics has helped reveal why some DNA mutations cause cancer, and predict how a patient will respond to a particular cancer treatment. However, currently, only about 2% of metabolites detected in a typical experiment can actually be identified. Michael uses machine learning methods to identify the remaining majority of metabolites that are not currently identifiable. Michael’s project could substantially increase the efficiency of metabolomics studies of cancer and lead to the discovery of new treatments for many different types of cancer.

Artem Babaian is a two-time Roman M. Babicki Research Fellow. Artem researches Acute Lymphoblastic Leukemia, a common childhood blood cancer requiring aggressive chemotherapy. There is an urgent need to develop precision medicines which target cancerous cells while preserving healthy ones, to mitigate the long-term harm caused by standard chemotherapy. During the course of holding his first Roman M. Babicki Fellowship, Artem discovered a cancer-specific ribosomal RNA variant which correlates with tumour-growth, thus finding what may be a significant and unexpected feature of cancer development. The results of this discovery are highly novel and if successful may fundamentally improve cancer therapies by establishing a new class of chemotherapies against this novel target and help minimize treatment toxicity in young patients.

Erin Marshall researches lung cancer, the leading cause of cancer death worldwide. Although inflammatory lung diseases (such as chronic obstructive pulmonary disease - COPD) have been associated with an increased risk of lung cancer development, the reasons why COPD airway damage leads to lung cancer remains unknown. Erin studies patients with both COPD and lung cancer, identifying changes in gene expression and immune cells content that may lead to cancer development. This will allow for the identification of relationships between the genes present in the airways of patients suffering from COPD and early-stage cancers, possibly revealing new avenues to prevent cancer initiation through the inhibition of those specific genes. Erin’s project holds the potential to explain why COPD predisposes patients to lung cancer, and may reveal new targets for cancer therapy and methods of cancer prevention.

Artem Babaian researches Hodgkin Lymphoma, a B-cell cancer affecting predominantly young adults. The actual Hodgkin Lymphoma cells are very rare within tumours, making it difficult to molecularly sub-classify the cancer and hinders clinical therapy decision making, leading to some patients receiving too much chemotherapy and doing harm in the long-term, while other patients failing to receive needed aggressive interventions. Artem’s research focuses on transposable elements in the human genome, the so-called “Junk DNA.” He has discovered that a class of these ancient DNA elements is specifically re-activated in cancers and can also activate nearby cancer causing genes. Using RNA-sequencing data, he has identified a panel of 15 such genes that are likely to contribute to Hodgkin Lymphoma development. Building on this discovery, Artem is developing a novel class of biomarker which exploits cancer-specific transposable element sequences to molecularly classify specifically the Hodgkin Lymphoma cells from complex clinical samples, which will help patients and physicians make better informed decisions for therapy selection, and overall improve patient outcomes.

Nilgoon Zarei’s research is engaged in developing more affordable and reliable prognostic tools for detecting prostate cancer, the third leading cause of cancer mortality in North America. Current procedures depend on analyses of tissue morphological structures, which are very subjective and which often lead to under-treatment or over-treatments in cancer patients. While it has been shown that Qualitative Digital Pathology of prostate cancer images has the potential to produce prognostic and predictive outcomes that could help calibrate more precise and effective treatment, several other techniques need to be developed in order for this to become an operative form of technology for this purpose. To this end, Ms. Zarei is working on developing objective, automated, and cost-effective Qualitative Digital Pathology tools to provide reliable prognostic information for prostate cancer, with the potential to improve the life quality of patients significantly, all while decreasing related medical costs.

Hye-Jung (Elizabeth) Chun’s research focuses on malignant rhabdoid tumours (MRTs), which are childhood cancers that resist known chemotherapies and spread quickly to other areas of the body (i.e. metastasis). MRTs arise frequently in kidneys and the brain, but the cell type that gives rise to MRTs is currently unknown, which poses challenges in understanding molecular aberrations that can be therapeutically targeted. Despite MRT’s highly malignant characteristics, loss of a protein called SMARCB1 is responsible for MRT development. Characterizing molecular profiles of MRTs is important to understand mechanisms behind the pathology of this fast-progressing cancer type. To date, her research has revealed surprising molecular diversities in MRTs that resulted from SMARCB1 loss, and indicated dysregulation of developmental pathways, particularly those of embryonic stem cells and neural crest cells, a putative cell type of origin for MRTs. The data generated from her research and the observations made from her analyses contribute to enhanced understanding of MRT biology, which she hopes will ultimately aid in development of better therapies for MRT patients.

Haolong Li studies advanced prostate cancers, the primary treatment for which is castration therapy, which in turn inhibits the actions of a protein inside cancer cells known as the androgen receptor (AR). There are several AR inhibitors used in clinical practice that can effectively delay tumor growth. Unfortunately, such benefits only last for a short period of time. Tumors eventually find alternative ways to re-activate AR activity. Previous studies show that AR requires another protein called Topo II to start its function. His new studies further indicate that Topo II inhibitors can block AR function and suppress prostate tumor growth including the drug resistant tumors. To get the ideal Topo II inhibitors that have higher efficiency and lower toxicity than the current ones, Haolong has co-developed a computer-aided drug screening system to target Topo II. Higher scored compounds evaluated from the system exhibit better performance in biological tests, proving the accuracy and precision of the whole screening process. Therefore, he now propose using this established system to screen up to 100 million compounds for new generation Topo II inhibitors and ultimately for treating prostate cancer patients.

Karissa Milbury researches Dis3, an enzyme that is commonly mutated in the blood cancer multiple myeloma. Dis3 acts as an RNA supervisor in the cell: it helps process RNA to make sure it is transported to the right place, and it degrades RNA that has been created inappropriately or outlived its usefulness. Her research group has found that mutations that cripple Dis3 also cause RNA to get stuck to the DNA, creating damage-prone structures called R-loops. She aims to identify why and how Dis3 affects R-loops, because this would directly link a mutation seen in multiple myeloma with the DNA damage that makes cancers dangerous.

Ling-I Olivia Tseng researches the associated risk of osteoporosis in some forms of breast cancer treatment. Her work has shown that osteoporosis screening rates are still below 30% for women treated for breast cancer in British Columbia. Patient notices with information packages have been shown to increase osteoporosis screening rates from 22% to 51% for patients with prior fractures. However, it is unclear whether information packages can improve osteoporosis screening for women with a prior breast cancer history. A research study has been designed to answer this research question. Before conducting a large-scale study, her research group is conducting a pilot study to determine: 1) the acceptance of the study procedures and 2) the willingness of participating in this study among women with a prior breast cancer history. This study can potentially help family doctors identify women with elevated risk of fractures in this unique group.

As a Ph.D. candidate in the department of Pathology and Laboratory Medicine, Jay Gunawardana studied malignant lymphomas, the fourth most frequent type of cancer in men and women that affects patients of all ages. Lymphomas are diverse in their biology and clinical behaviour and unfortunately, the current standard of care fails to eliminate it in a substantial proportion of patients who are then very likely to succumb to their disease. The causes for these unfavorable clinical outcomes are partly due to the lack of novel therapeutic targets.

Dr. Gunawardana’s work focused on improving the survival of patients with a specific type of lymphoma, called primary mediastinal large B-cell lymphoma (PMBCL). Along with his research team, he discovered novel mutations in a subset of PMBCL patients that activates oncogenic signaling ("JAK-STAT signaling") and leads to aberrant PMBCL tumour cell signaling and tumor growth. He also examined how these gene mutations contribute to the formation of these cancers and how knowledge about JAK-STAT signaling can help identify drug targets to improve therapies for affected patients. Ultimately, he hopes his findings will provide a rational therapeutic target for future treatments; maximizing cure rates and minimizing treatment-related side effects.

Mani Roshan-Moniri is a PhD candidate in Experimental Medicine Program, in the department of Urologic Sciences. Mr. Roshan-Moniri’s work focusses on understanding the mechanism of action of candidate drug compounds for prostate cancer that targets the distinct protein ETS-related gene (ERG). Over 50% of all prostate cancer involves a genomic irregularity in the ERG. This alteration results in the overexpression of ERG in the prostate where it acts to promote disease metastasis. Androgen deprivation therapy (ADT) acts by inhibiting the production of androgens or by blocking the interaction of androgens with androgen receptors, and it is the standard treatment for locally advanced, recurrent and metastatic prostate cancer. However, it is only initially effective, as resistance to ADT often occurs. Mr. Roshan-Moniri therefore aims to develop candidate anti-ERG compounds as an entirely new generation of therapeutics that could either supplement or replace the conventional resistance-prone androgen deprivation therapy for metastatic, castration-resistant prostate cancer patients