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Cancer Cell. 2006 May;9(5):341-9.

A dual PI3 kinase/mTOR inhibitor reveals emergent efficacy in glioma.

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1
Department of Neurology, University of California, San Francisco, San Francisco, California 94143, USA.

Abstract

The PI3 kinase family of lipid kinases promotes cell growth and survival by generating the second messenger phosphatidylinositol-3,4,5-trisphosphate. To define targets critical for cancers driven by activation of PI3 kinase, we screened a panel of potent and structurally diverse drug-like molecules that target this enzyme family. Surprisingly, a single agent (PI-103) effected proliferative arrest in glioma cells, despite the ability of many compounds to block PI3 kinase signaling through its downstream effector, Akt. The unique cellular activity of PI-103 was traced directly to its ability to inhibit both PI3 kinase alpha and mTOR. PI-103 showed significant activity in xenografted tumors with no observable toxicity. These data demonstrate an emergent efficacy due to combinatorial inhibition of mTOR and PI3 kinase alpha in malignant glioma.

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PMID:
16697955
PMCID:
PMC2925230
DOI:
10.1016/j.ccr.2006.03.029
[Indexed for MEDLINE]
Free PMC Article
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