The proposed platform will 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 through personalized medicine.
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. In the development of new experimental agents, there is a desperate need to identify which patients would respond best to a given treatment. This personalized medicine approach is not a simple process, as each cancer type represents a unique disease which harbours a variety of genetic mutations. One approach taken by Dr. Shore and his team is based on synthetic lethality. This refers to a requirement that two genes, if eliminated individually, have little impact on cancer cells, but together their elimination results in cell lethality.
This new platform uses preclinical proof-of-concept models to identify what drug combinations would be most effective in patients. The team has successfully completed work on two gene knock-down and screening methodologies for the discovery process: human genome-wide siRNAs screened in high-throughput format and targeted lentiviral shRNAs screened in a pooled format. These screens target an astounding number of key genes involved in tumorigenesis, which include regulators of protein synthesis and translation control, protein tyrosine phosphatases, and cell death regulators, as well as many others. Early proof-of-concept studies have been initiated in multiple myeloma with a focus on genetic markers of sensitivity to dexamethasone, a widely used anti-cancer agent in multiple hematological cancer indications. To date, the team has identified two promising drug combination strategies with dexamethasone, one involving the inhibition of survival protein Mcl-1 and a second associated with the inhibition of Aurora B kinase, a protein integrally involved in mitosis and cytokinesis. Future work will concentrate on the in vivo validation of both strategies in relevant murine cancer models.
Impact on the drug discovery process