Synthetic lethality platform to discover, test and validate new therapeutic treatment options for cancer

Challenge: In recent years, only 8% of new oncology drugs have been approved for clinical use. One of the major challenges has been matching an appropriate therapeutic strategy to a cancer indication due to the heterogeneity of the disease. Nevertheless, the personalized medicine approach is not a simple process, as each cancer type represents a unique disease that harbors a variety of genetic mutations that can each influence treatment responses.

Solution: The research team developed an approach based on synthetic lethality, which requires that two genes if eliminated individually, have little impact on cancer cells, but result in cell lethality when impaired together. A platform has been developed to allow the identification of cellular pathways and gene targets acting in synergy with new or existing drugs for cancer therapy. This platform could also generate novel biomarkers to predict treatment response to specific therapies.

Achievements/Impact: The integrated platform in synthetic lethality was successfully established by first constructing focused shRNA libraries (targeting approx. 400 genes) and complemented by commercially available siRNA libraries to carry out functional genomic screens of these libraries in pooled formats. This allowed the researchers to establish a proof of concept in multiple myeloma by identifying a list of dexamethasone synthetic lethality candidate genes whose inhibition results in either a sensitizing or resisting effect of cells to DEX treatment. This screening platform was instrumental in generating a promising discovery for Diazon Pharmaceuticals, a Montreal start-up funded by Sanderling, a top-tier American venture firm. It also allowed McGill University to establish a multi-million dollar, multi-year research agreement with Diazon to determine the mechanism of action of DZ-2384 and to investigate relevant cancer indications for development in the clinic.