Analysis of PI3K Inhibitors to Inform Translation into the Clinic
Kurt Auger,
Manager
GlaxoSmithKline R&D
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Abstract: Kurt R. Auger, Cancer Research, GlaxoSmithKline
The phosphoinositide 3-kinase (PI3K) signaling pathway is constitutively activated in a broad spectrum of human cancer and this pathway is critical for cell survival and transformation. Inhibiting PI3K is a promising therapeutic strategy for the treatment of cancer. GSK1059615, a novel inhibitor of the class I family of PI3K enzymes is a potent, ATP-competitive small molecule inhibitor that reversibly inactivates PI3K. The biochemical inhibition of enzyme activity effectively translates to activity in cellular assays, and oral dosing in mice decreases tumor pAKT levels and inhibits the growth of human tumor xenografts. Analysis of cell lines identifies mutant Ras and Raf as genetic markers associated with decreased sensitivity. Accordingly, we have evaluated the efficacy of combining GSK1059615 with the recently described GSK MEK inhibitor in cell culture models and the combination was found to be highly effective. The biomarkers identified for the PI3K response will be discussed for translation and clinical evaluation.
Presenter Biography: Current * Manager at GlaxoSmithKline
Past * Principal Scientist at Bristol-Myers Squibb
* Principal Research Scientist at DuPont Pharmaceuticals
* Instructor in Cellular and Molecular Biology at Dana-Farber Cancer Institute and Harvard Medical School
Education
* Harvard Medical School and Dana-Farber Cancer Institute
* Tufts University Sackler School of Graduate Biomedical Sciences
* University of New Hampshire
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