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Research Articles: Therapeutics, Targets, and Development

Characterization of structurally distinct, isoform-selective phosphoinositide 3'-kinase inhibitors in combination with radiation in the treatment of glioblastoma

Departments of ¹ Radiation Oncology, ² Molecular and Cellular Pharmacology, and ³ Neurology and ⁴ Cancer Research Institute, Comprehensive Cancer Center at the University of California at San Francisco, San Francisco, California

Requests for reprints: David Stokoe, Genentech, Inc., Department of Molecular Biology, 1 DNA Way, South San Francisco, CA 94080. Phone: 650-225-6031; Fax: 650-225-6412. E-mail: stokoe.david@gene.com

Abstract

The phosphoinositide 3'-kinase (PI3K)–mediated signaling pathway plays a key role in fundamental cellular functions important in normal cellular homeostasis and malignant transformation. Deregulated signaling through this pathway contributes to development of gliomas and their resistance to radiation and chemotherapy. Targeting the PI3K signaling pathway has thus emerged as a promising approach to successful treatment of gliomas. We assessed the radiosensitizing potential of four small-molecule inhibitors that differ in their activities against specific isoforms of the PI3K 110-kDa catalytic subunit (p110). p110 inhibitors blocked phosphorylation of both protein kinase B/Akt and S6 in all cell lines examined, effectively decreased cellular proliferation, and produced additive cytotoxic effects in combination with radiation therapy. The p110β inhibitor exhibited limited biochemical effects and failed to decrease cellular proliferation or viability as either a single agent or in combination with radiation or rapamycin. In vivo studies examining the effects of the p110 inhibitor in combination with radiation indicated a significant reduction in tumor growth rate induced by the combined treatment compared with each treatment modality alone. This translated into a trend toward prolonged time-to-failure for mice in the combination treatment group. In conclusion, PI3K inhibitors are promising agents in the treatment of glioblastomas, especially when used in combination with ionizing radiation. [Mol Cancer Ther 2008;7(4):841–50]

Grant support: NIH grant PO1 NS-42927-27A2 (D. Haas-Kogan), NIH Brain Tumor SPORE grant P50 CA097257 (D. Haas-Kogan and D. Stokoe), The Nancy and Stephen Grand Philanthropic Fund (D. Haas-Kogan), RO1CA79548 (D. Stokoe), DOD TS030017 (D. Stokoe), Dutch Cancer Society (M. Donker), and Saal van Zwanenberg Foundation (M. Donker).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

Note: J. Chen and L.J. Zhou contributed equally to this work.

Current address for M. Donker: Department of Radiation Oncology, Academic Medical Center, University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands.

⁵ Supplementary material for this article is available at Molecular Cancer Therapeutics online (http://mct.aacrjournals.org/).

Received 6/11/07; revised 11/26/07; accepted 2/25/08.