Finding new treatment options for glioblastoma through data-driven discovery

Glioblastoma multiforme (GBM) is an extremely aggressive type of brain cancer with no known cure. Despite years of research, there are still no treatments tailored to the unique genetics of a patient’s tumour, meaning that even after aggressive treatments, the cancer returns, leading to an extremely poor prognosis. 

A new team of pan-Canadian researchers funded through the Marathon of Hope Cancer Centres Network aims to change this, using data generated by Network-supported projects across the country to bring new hope to patients affected by this deadly disease.

“The main goal of our project is to use the rich data that are part of the Network’s Gold Cohort to find new ways to match more drugs to more GBM patients, even if those drugs weren’t originally designed for GBM,” says Dr. Marco Marra (University of British Columbia and BC Cancer), who will lead the team.

In collaboration with Drs. Sherri Christian (Memorial University of Newfoundland), Anthony Reiman (University of New Brunswick), and Jennifer Chan and Sorana Morrissy (University of Calgary), the team will analyze whole genome sequencing data from approximately 120 GBM cases from across the country that are part of the Network’s Gold Cohort. They are amongst the first teams to have access to this combined dataset, after being named as one of the Network’s Data Sharing and Use Pilot projects.

“Over the last four years, the Network has united patients, researchers, clinicians and administrators across the country to generate an unprecedented dataset,” explains Dr. Marra. “We are excited to start using these data in our mission to advance cancer research and care.”

Data-driven discoveries for the benefit of cancer patients

As part of the project, the team will use a computational tool called GRETTA to perform personalised analyses, seeking to identify potential vulnerabilities that arise from the unique genomic alterations in each individual’s tumour, and then assessing whether drugs exist that can target these vulnerabilities and kill or inhibit the growth of cancer cells.

The team’s approach leverages a concept called “synthetic lethality”, in which two genetic alterations in combination impede the growth of, or kill, cancer cells. The team will use an existing on-line data resource (DepMap) made available by international researchers, which contains genomic and cell viability data for nearly 2,000 cancer cell lines. For each cell line, in addition to providing comprehensive lists of mutations and gene expression data, DepMap researchers have inactivated (i.e. “knocked out”) all genes in the genome and measured the effect of every inactivation on cancer cell growth.

The team’s strategy will be to find mutations in GBM samples from the Gold Cohort, and then identify DepMap GBM cells with the same or similar mutations. Next, the team will identify gene knock outs in these cell lines that reduce the viability of the DepMap GBM cell. These knock outs identify genes that, when inactivated, represent possible vulnerabilities that may be exploited using existing drugs or other interventions. And, because these mutations and knock out combinations ought not to exist in non-cancer cells, interventions that target them might have reduced or fewer toxic side effects. Unique to this team’s data-driven approach is the ability to search for drug that are unconventional for GBM treatment. The team intends to promote the consideration of these “out-of-the-box” but approved drugs that may be useful to individual cancer patients, thus advancing precision genomic medicine for patients with GBM.

In the longer term, the researchers hope their findings may expand the number of candidate drug options available to GBM patients and strengthen Canada’s ability to deliver data-driven, personalized cancer care.

“This is a very important pilot project, but it is really just the beginning,” says Dr. Marra. “We envision this proposal as the start of a larger effort, in which we eventually scale our approach across other network sites and cancer types.”

Of critical importance, the project will also test how well MOHCCN members across the country can share and use data together—helping to pave the way for future pan-Canadian collaboration in precision oncology.

“Our project shows how unfettered access to data can be leveraged across countries and within Canada. DepMap, which was funded by the Broad Institute (USA) and Wellcome Sanger Institute (UK) has generated extremely useful data which we can freely use to innovate here in Canada. We now want to show that we can use Network data to innovate. I expect these pilot projects will prove instructive and serve to refine Canadian data sharing strategies. Network funding is critical because it uniquely supports cross-Canada collaboration through harmonized data and resources, enabling both our analytic platform and sharing of our results with the collaborating sites and beyond, extending to the entire Network and through the Network to Canadians,” says Dr. Marra. “This investment thus helps ensure that our results have the potential to be rapidly translated into benefits for Canadians, particularly those affected by cancer.