Grant: Foundation Grant

Clonal Dynamics; Computational Biology; Dna Repair; Genomic Instability; Genomic Signatures; Homologous Recombination; Next-Generation Sequencing; Ovarian Cancer; Response Prediction; Tumour Evolution

<html> <body> <p> <strong>Program Direction and Major Research Questions:</strong> <br> I aim to understand how high grade serous ovarian cancers evolve. High grade serous cancers are the most lethal histotype of ovarian cancer, where up to 80% of cases suffer relapse after initial response to treatment with many patients succumbing to treatment resistant disease. It is believed that clonal evolution underpins treatment resistance, but we have little understanding about the relative fitness of clones that comprise tumours at diagnosis. More importantly, the dynamic growth trajectories of clones found within peritoneal foci have not been studied systematically when challenged with chemotherapeutic selective pressures. As such, beyond anecdotal evidence of BRCA revertant mutations, most relapses and their underlying mechanisms remain unexplained. I have outlined a multi-disciplinary programmatic approach to addressing these knowledge gaps which will leverage local expertise in ovarian cancer pathology, gynecologic oncologic surgery, patient derived xenografts, next generation sequencing and computational biology. This program will result in an unprecedented view of high grade serous ovarian cancer evolution as it relates to the challenges of microenvironmental and therapeutic selective pressures.<br> <br> The major questions I will explore are as follows:<br> 1) What are the relative fitness properties of clones that have established in ovarian and other peritoneal foci at diagnosis?<br> 2) To what degree are competition and co-operation driving clonal growth trajectories over time?<br> 3) How are fitness properties and clonal expansions affected by selective pressures induced by chemotherapy?<br> 4) What genetic alterations underpin fitness and clonal dynamics in treatment sensitive and treatment resistant clones?<br> <br> <strong>Program Vision:</strong> <br> I have outlined a systematic program of research to address these fundamental and clinical questions in ovarian cancer biology. The program builds off of my successful CIHR Operating Grant to study ovarian cancer evolution and to develop methods for ascertainment of clonal genotypes using next generation sequencing devices. The program is based on five key objectives that will leverage the diverse and leading edge research expertise of my laboratory and the assembled program experts:<br> <br> <strong>Objective 1:</strong> Amplify an ongoing recruitment of patient material to establish patient-derived xenograft lines from multiple anatomic HGSC sites<br> <strong>Objective 2:</strong> Perform mutational profiling of bulk and single cell material from Objective #1 to identify clones as substrates of selection<br> <strong>Objective 3:</strong> Develop a suite of computational methods for phylogenetic inference and determination of relative fitness of clones from growth trajectories over time<br> <strong>Objective 4:</strong> Determine the reproducibility of selection and the fitness properties of clones in timeseries PDX models in treatment na&iuml;ve and chemotherapeutic contexts<br> <strong>Objective 5:</strong> Associate genotypes with fitness advantages and validate in larger cohorts<br> <br> <strong>Core Expertise/Team and Partnerships:</strong> <br> I have assembled a high-calibre team of investigators with expertise in: gynecologic oncology and surgery and tumour tissue banking (McAlpine), genome sequencing (Marra), patient-derived xenografts and tumour evolution (Aparicio), molecular pathology (Huntsman), single cell sequencing and microfluidics (Hansen), computational phylogenetics and Bayesian non-parametric statistics (Bouchard-Cote), and model systems for functional genomics (Hieter).</p> </body> </html>