Isoform specific inhibitors of PI3 kinase in glioma

Abstract

The PI3 kinase pathway is among the most frequently activated signaling pathways in human cancer and represents an attractive target for small molecule inhibitor based therapies. The PI3Ks show considerable diversity however, and it remains unclear which kinases in this family should be targeted in cancer. We recently screened a panel of potent and structurally diverse drug-like molecules that target this enzyme family in glioma, a malignancy that shows frequent activation of PI3K signaling. Although PI3Kα was the major isoform driving malignant progression in glioma, blockade of PI3Kα was not sufficient to maximally inhibit glioma cells. A single agent that inhibited both PI3Kα and mTOR targeted two points in a pathway with multiple levels of feedback, and was essential for shutting down the proliferation of glioma cells. This result suggests a potentially effective strategy for cancer therapy based on dual inhibition of these two PI3K family members. ©2006 Landes Bioscience.