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Research Articles: Therapeutics, Targets, and Development

The combination of novel low molecular weight inhibitors of RAF (LBT613) and target of rapamycin (RAD001) decreases glioma proliferation and invasion

Departments of ¹ Surgery, ² Pathology, ³ Pediatrics, ⁴ Medicine, and ⁵ Neurobiology and ⁶ Preston Robert Tisch Brain Tumor Center, Duke University Medical Center, Durham, North Carolina; and ⁷ Novartis Institutes for Biomedical Research, Cambridge, Massachusetts

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

Abstract

Monotherapies have proven largely ineffective for the treatment of glioblastomas, suggesting that increased patient benefit may be achieved by combining therapies. Two protumorigenic pathways known to be active in glioblastoma include RAS/RAF/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/AKT/target of rapamycin (TOR). We investigated the efficacy of a combination of novel low molecular weight inhibitors LBT613 and RAD001 (everolimus), which were designed to target RAF and TOR, respectively. LBT613 decreased phosphorylation of extracellular signal-regulated kinase 1 and 2, downstream effectors of RAF, in a human glioma cell line. RAD001 resulted in decreased phosphorylation of the TOR effector S6. To determine if targeting RAF and TOR activities could result in decreased protumorigenic glioma cellular behaviors, we evaluated the abilities of LBT613 and RAD001 to affect the proliferation, migration, and invasion of human glioma cells. Treatment with either LBT613 or RAD001 alone significantly decreased the proliferation of multiple human glioma cell lines. Furthermore, LBT613 and RAD001 in combination synergized to decrease glioma cell proliferation in association with G₁ cell cycle arrest. Glioma invasion is a critical contributor to tumor malignancy. The combination of LBT613 and RAD001 inhibited the invasion of human glioma cells through Matrigel to a greater degree than treatment with either drug alone. These data suggest that the combination of LBT613 and RAD001 reduces glioma cell proliferation and invasion and support examination of the combination of RAF and TOR inhibitors for the treatment of human glioblastoma patients. [Mol Cancer Ther 2007;6(9):2449–57]

Grant support: Pediatric Brain Tumor Foundation of the United States (J.N. Rich); Accelerate Brain Cancer Cure (J.N. Rich); Childhood Brain Tumor Foundation (J.N. Rich); Southeastern Brain Tumor Foundation (A.B. Hjelmeland); and NIH grants NS047409, NS054276, CA108786, and CA116659 (J.N. Rich). A.B. Hjelmeland is a Paul Brazen/American Brain Tumor Association Fellow. J.N. Rich is a Damon Runyon-Lilly Clinical Investigator supported by the Damon Runyon Cancer Research Foundation and a Sidney Kimmel Foundation for Cancer Research 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 18 U.S.C. Section 1734 solely to indicate this fact.

⁸ http://rsb.info.nih.gov/ij/

⁹ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/)

Received 3/ 6/07; revised 7/16/07; accepted 7/25/07.