Grant: Foundation Grant

<html> <body> <p>My overarching research <strong>ambitions</strong> are to understand the roles of genetic alterations in promoting cancer and to translate this understanding for patient benefit. My program&rsquo;s <strong>direction</strong> includes analysis of the functional interplay between the genome and the epigenome.<br> </p> <p> <strong>Background:</strong> We used genomics to characterize human cancers and revealed high frequencies of somatic mutations in transcriptional regulators, particularly chromatin modifiers, implying such mutations drive cancers. This, and similar data from others, indicates that the relationship between the genome and the epigenome is exploited by cancer cells. Now we propose to understand the details of such relationships, with the goal of producing new knowledge that both informs on the biology of genome regulation and has the potential to inform patient care.<br> </p> <p> <strong>Questions and Objectives:</strong> The questions motivating this research are: How do somatic mutations in transcriptional regulators, in particular epigenome readers, writers or erasers, promote cancer; and: Can we design approaches to interfere with malignant progression driven by such mutations? Our objectives are to (1) obtain experimental models for genes of interest and use these to (2) assess the functional impact of recurrent mutations in epigenome regulators; (3) identify proteins and pathways that interact with mutant proteins and genes; and (4) develop approaches to inhibit or otherwise modulate such proteins / pathways.<br> </p> <p> <strong>General approach:</strong> Focusing on recurrently mutated genes, we will exploit model systems we will create using recently available genome engineering technologies. Characterizing genomes, epigenomes, transcriptomes, proteomes and metabolic profiles of such models and patient samples will reveal both mechanistic insights and therapeutic strategies relevant to cancer. Further understanding of the pathways involved will be achieved through both genome wide knock-down / knock out screens to identify genetic and synthetic lethal (SL) interactions in our model cells, and screens using already available epigenetic tool compounds. Discoveries will be validated using panels of engineered and patient derived cell lines, and selected interactions will be verified at the protein level. My program will ideally reveal proteins and pathways that can be inhibited and possibly drugged to retard the growth of mutant cells, thereby promoting the development of new therapeutic strategies for cancers.<br> </p> <p> <strong>Anticipated Outcomes:</strong> The outcomes anticipated from our work will substantially add to our understanding of cancer biology. The potential of program discoveries to influence patient care is significant as illustrated by our discovery of gain of function <em>EZH2</em> mutations in lymphoma patients, an observation that contributed to an ongoing clinical trial in which EZH2 inhibitors are now being tested in patients carrying these mutations. My program will benefit from the world-class research facilities and infrastructure available to us in our lab and at the BC Cancer Agency. It will also leverage the strengths (e.g. genome-wide screening, clinical expertise) and resources (e.g. patient samples) of collaborators both nationally and internationally. A substantial program of training (e.g. in functional genomics, cancer), mentoring, knowledge transfer, interdisciplinary learning opportunities and collaborations will bring together undergraduate and graduate students, postdoctoral fellows, oncologists, pathologists and technical staff.</p> </body> </html>