Integrated platform to identify synthetic lethality opportunities in cancer therapy
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OverviewThis integrated platform will apply the concept of synthetic lethality to discover, test and validate new therapeutic targets for cancer. The identification of these key cancer genes has the potential to significantly improve the efficacy of new and already existing anti-cancer drugs. |
Basic research has made important advances in understanding the causes of cancer, resulting in the discovery of a new generation of therapeutic drugs. Nevertheless, only modest progress has been made in reducing the mortality rate. Each cancer type represents a unique disease that harbours a variety of genetic mutations, and, as a result, a “one drug fits all” approach does not always mean a favourable outcome for patients. Typically, the development of a new anti-cancer agent involves clinical trials with a wide variety of subjects and drug combinations, a process that requires years before determining which patients benefit and where often the drug fails to be approved for clinical use because only a small number of patients respond. There is consequently a need to identify and predict the genetic characteristics of tumours likely to be susceptible to a given anti-cancer therapy and translate them into new personalized therapeutic opportunities.
Dr. Shore and his team will apply the concept of synthetic lethality to identify key cancer susceptibility genes. Large scale genomic screens will be undertaken to knock down the function of genes and reveal those that, when eliminated in the presence of a cancer therapeutic, enhance or accelerate its anti-cancer effect. Each new genetic target identified represents a new personalized therapeutic opportunity by i) targeting a specific cancer type commonly deficient in that gene, ii) utilizing the anti-cancer agent in combination with other agents targeted to the gene or pathway identified, or iii) providing a biological or genetic marker to select patients whose tumours are deficient in the identified gene.
Two gene knockdown and screening methodologies will be used: i) human genome-wide siRNAs screened in high-throughput format, and ii) lentiviral shRNAs screened in pooled format. The shRNA-focused libraries target over 400 important genes involved in tumorigenesis, including i) regulators of protein synthesis and translation control, ii) protein tyrosine phosphatases, and iii) cell death regulators. As a proof of concept, the first set of screens will search for genetic markers of sensitivity to dexamethasone, an anti-cancer agent widely used in oncology for multiple indications including leukemias, lymphomas and multiple myeloma. A second shRNA screen with a topo-isomerase inhibitor will further identify new therapeutic opportunities for this agent.
The development of this synthetic lethality platform brings together highly dedicated scientists from the Goodman Cancer Centre, each with deep knowledge of cancer pathways. “The strength of the platform lies in the integrated approach that combines the expertise of multiple investigators involved in fundamental research as well as collaborations with clinicians and scientists with industry-based regulatory and pre-clinical drug development experience,” says Dr. Gordon Shore, co-founder of Gemin X Pharmaceuticals and Professor of Biochemistry and Oncology at McGill University, adding: “Knowledge derived from this platform will help guide and accelerate the clinical development of new agents, improving their chance of success and scope of use.”
Impact on the drug discovery process
- Select potentially responsive patients in clinical trials thus improving the likelihood of clinical approval for new anti-cancer drug candidates
- Provide more effective drug combination strategies, increasing the scope of use for already approved anti-cancer agents
- Identify new anti-cancer targets for future anti-cancer therapeutic development
- Bring new personalized therapeutic options for patients
Key facts
- Cancer is a leading cause of death worldwide and accounted for approximately 13% of human mortality in 2008
- Each human tumour exhibits an average of 80 genetic alterations (mutations, deletions and amplifications), the majority of which are in genes involved in regulatory processes or pathways
- In recent years, only 3-8% of oncology drugs in clinical trials have been approved for clinical use. One of the major causes of oncology drug failure during the development process is lack of efficacy. There is a desperate need for more knowledge regarding which patients would best respond to new experimental agents
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