Article

Cellular and in vivo activity of a novel PI3K inhibitor, PX-866, against human glioblastoma

Department of Neuro-Oncology, Unit 100, The University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030, USA.
Neuro-Oncology (Impact Factor: 5.29). 02/2010; 12(6):559-69. DOI: 10.1093/neuonc/nop058
Source: PubMed

ABSTRACT The phosphatidylinositol-3-kinase (PI3K)/Akt oncogenic pathway is critical in glioblastomas. Loss of PTEN, a negative regulator
of the PI3K pathway or activated PI3K/Akt pathway that drive increased proliferation, survival, neovascularization, glycolysis,
and invasion is found in 70%–80% of malignant gliomas. Thus, PI3K is an attractive therapeutic target for malignant glioma.
We report that a new irreversible PI3K inhibitor, PX-866, shows potent inhibitory effects on the PI3K/Akt signaling pathway
in glioblastoma. PX-866 did not induce any apoptosis in glioma cells; however, an increase in autophagy was observed. PX-866
inhibited the invasive and angiogenic capabilities of cultured glioblastoma cells. In vivo, PX-866 inhibited subcutaneous
tumor growth and increased the median survival time of animals with intracranial tumors. We also assessed the potential of
proton magnetic resonance spectroscopy (MRS) as a noninvasive method to monitor response to PX-866. Our findings show that
PX-866 treatment causes a drop in the MRS-detectable choline-to-NAA, ratio and identify this partial normalization of the
tumor metabolic profile as a biomarker of molecular drug action. Our studies affirm that the PI3K pathway is a highly specific
molecular target for therapies for glioblastoma and other cancers with aberrant PI3K/PTEN expression.

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