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

作者：Dimpy Koul, Ruoqi Shen, Young‐Woo Kim, Yutaka Kondo, Yue Lu, James A. Bankson, Sabrina M. Ronen, David Kirkpatrick, Garth Powis, W. K. Alfred Yung · 发表于：Neuro-Oncology · 年份：2010 · DOI：10.1093/neuonc/nop058 · 被引用次数：129 · 研究领域：PI3K/AKT/mTOR signaling in cancer、Autophagy in Disease and Therapy、CRISPR and Genetic Engineering

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.