Targeted therapy for the treatment of cancer and metastasis can be divided into two main categories: monoclonal antibodies and small molecules. In this talk, we will discuss the approach of employing synthetic lethality to target cancer, specifically renal cell carcinoma. The concept of synthetic lethality is used to describe a genetic interaction of two non-allelic and non-lethal genes that when mutated simultaneously results in cell death. Recently, we screened for small molecules that function in a synthetic lethal manner to the loss of VHL, a mutation responsible for the vast majority of renal cell carcinoma. In this screen, we identified several small molecules, which demonstrated selective toxicity against cells that had lost VHL compared to isogenic matched cell lines with wild-type VHL both in vitro and in vivo. One ofthese small molecules kills VHL deficient cells by inducing autophagy and another kills by inhibiting glucose uptake and retention. Both of these small molecules illustrate the power of using synthetic lethality in mammalian cells to develop new therapeutic strategies.

Targeting the VHL/PHD/HIF pathway therapeutically

247th National Meeting (2014)

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