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Departments of ¹ Pathology, ² Surgery, ³ Pediatrics, ⁴ Pharmacology and Cancer Biology, and ⁵ Neurobiology and ⁶ Division of Neurology, Duke University Medical Center, Durham, North Carolina; ⁷ University of Texas M.D. Anderson Cancer Center, Houston, Texas; ⁸ Novartis Institutes for Biomedical Research, Oncology, Novartis Pharma AG, Basel, Switzerland; and ⁹ Ludwig Institute for Cancer Research, University of California at San Diego, La Jolla, California

Requests for reprints: Jeremy N. Rich, Division of Neurology, Duke University Medical Center, P.O. Box 2900, Durham, NC 27710. Phone: 919-681-1693; Fax: 919-684-6514. E-mail: rich0001{at}mc.duke.edu

Malignant gliomas are highly lethal tumors that display striking genetic heterogeneity. Novel therapies that inhibit a single molecular target may slow tumor progression, but tumors are likely not dependent on a signal transduction pathway. Rather, malignant gliomas exhibit sustained mitogenesis and cell growth mediated in part through the effects of receptor tyrosine kinases and the mammalian target of rapamycin (mTOR). AEE788 is a novel orally active tyrosine kinase inhibitor that decreases the kinase activity associated with the epidermal growth factor receptor and, at higher concentrations, the vascular endothelial growth factor receptor 2 (kinase domain region). RAD001 (everolimus) is an orally available mTOR inhibitor structurally related to rapamycin. We hypothesized that combined inhibition of upstream epidermal growth factor receptor and kinase domain region receptors with AEE788 and inhibition of the downstream mTOR pathway with RAD001 would result in increased efficacy against gliomas compared with single-agent therapy. In vitro experiments showed that the combination of AEE788 and RAD001 resulted in increased rates of cell cycle arrest and apoptosis and reduced proliferation more than either agent alone. Combined AEE788 and RAD001 given orally to athymic mice bearing established human malignant glioma tumor xenografts resulted in greater tumor growth inhibition and greater increases in median survival than monotherapy. These studies suggest that simultaneous inhibition of growth factor receptor and mTOR pathways offer increased benefit in glioma therapy.

Key Words: Glioma • EGFR • mTOR • AEE788 • RAD001 • 00-00-02 Brain/central nervous system cancers

Grant support: Pediatric Brain Tumor Foundation of the United States (J.N. Rich and D.D. Bigner); Accelerate Brain Cancer Cure (J.N. Rich); Southeastern Brain Tumor Foundation (J.N. Rich); NIH grants NS047409 (J.N. Rich), CA14236 (C.J. Wikstrand), NS30245-15 and CA94231-02 (H.S. Friedman), NS20023 and CA11898, and M01 RR 30; GCRC Program; National Center for Research Resources; National Cancer Institute Specialized Programs of Research Excellence 1 P20 CA096890; and FCG grants (D.D. Bigner). R.K. Goudar was a Howard Hughes Medical Institute Medical student fellow. J.N. Rich is a Damon Runyon-Lilly Clinical Investigator and a Sidney Kimmel Cancer Foundation Scholar.

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 U.S.C. Section 1734 solely to indicate this fact.

Note: R.K. Goudar, Q. Shi, and M.D. Hjelmeland contributed equally to this work.

³ C. Wikstrand, unpublished data.

⁴ Software downloaded from http://rsb.info.nih.gov/ij.

⁵ C. Wikstrand et al., unpublished data.

⁶ C. Wikstrand et al., unpublished data.

Received 8/23/04; revised 10/11/04; accepted 11/ 3/04.