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The Prognostic Significance of Phosphatidylinositol 3-Kinase Pathway Activation in Human Gliomas

From the Departments of Radiation Oncology and Biostatistics, Massachusetts General Hospital/Harvard Medical School; Department of Neurosurgery, Brigham and Women's Hospital/Harvard Medical School, Boston, MA.

Address reprint requests to Arnab Chakravarti, MD, Massachusetts General Hospital, Department of Radiation Oncology, 100 Blossom St, Founders House, Room 536, Boston, MA 02114; e-mail: achakravarti{at}partners.org

PURPOSE: The objectives of this study were to examine activation patterns of the phosphatidylinositol 3-kinase (PI3K) pathway in gliomas and to examine the prognostic significance of PI3K pathway activation using snap-frozen clinical specimens.

MATERIALS AND METHODS: Levels of expression of PI3K pathway members were assessed in 92 prospectively collected gliomas through quantitative Western analysis using total and phospho-specific antibodies for PI3K, Akt, and p70^s6k. Both expression and expression levels of these PI3K pathway members were correlated with histology, markers of apoptosis (cleaved caspase 3), and with clinical outcome (eg, overall survival).

RESULTS: It was determined that activation of all three PI3K pathway members were significantly more frequent in glioblastoma multiforme than in non-glioblastoma multiforme tumors. Levels of phospho-PI3K, phospho-Akt, and phospho-p70^s6k were all found to be inversely associated with cleaved caspase 3 levels, suggesting PI3K pathway activation is associated with reduced levels of apoptosis. Perhaps most importantly, activation of PI3K pathway members was found to be significantly associated with reduced survival times when all glioma cases were considered in aggregate. When glioblastoma cases were considered separately, the prognostic value of PI3K activation remained significant, suggesting that PI3K activation may directly be associated with radiation resistance, given that this was the only adjuvant therapy administered to this subset of patients.

CONCLUSION: Activation of the PI3K pathway is significantly associated with increasing tumor grade, decreased levels of apoptosis, and with adverse clinical outcome in human gliomas. Molecular pathways regulating PI3K activation would appear to be promising targets in the clinical management of glioma patients.

Supported by the following grants: NIH KO8CA82163, Massachusetts General Hospital Brian D. Silber Memorial Fund, and Goldhirsh Foundation Award (all to A.C.).

Authors' disclosures of potential conflicts of interest are found at the end of this article.

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