Grant: Terry Fox New Investigator Award

Glioblastoma (GBM) is the most lethal form of brain tumor. On average, patients survive only 15 months after diagnosis because most tumors inevitably recur after surgery. Intra-tumor heterogeneity is believed to cause this dismal outcome: GBMs are complex tumors that are made up of many different types of cells. Some of these cells likely escape surgery and chemotherapy and evolve into secondary tumors that ultimately kill patients. However, the mechanisms of recurrence remain unknown. In this project, we build genetic maps of primary and recurrent GBMs to understand tumor recurrence and to find novel target genes for further study. We will first perform genome sequencing of primary and recurrent GBMs from the same patients. We will build the largest dataset of this kind by also collecting and analyzing data from existing studies. We will then map distinct cell populations in the tumors and statistically predict which mutations in these cells likely caused tumor recurrence. Second, we will develop new computational algorithms that jointly analyze the genetic maps of primary and recurrent GBMs with additional molecular information of the same tumors already collected by the sponsoring TFRI team. Third, using these large and complex datasets with our new algorithms, we will find genes and molecular pathways that are involved in GBM recurrence, and distinguish those for which cancer drugs already exist. Our detailed catalogue of genes, pathways and networks serves as a resource of hypotheses that enable the sponsoring TFRI team to conduct molecular experiments with the ultimate goal of understanding and treating tumor recurrence. Our algorithms are useful to study metastasis in other cancer types and will be made freely available to the research community. If any predicted candidate genes are already known as targets of cancer drugs, these may be available to the specific GBM patients compassionately in collaboration with expert clinician-scientists.