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Dual Inhibition of PI3K and mTOR as an Alternative Treatment for Kaposi's Sarcoma

¹ Department of Oncology and Diagnostic Sciences and ² Greenebaum Cancer Center, University of Maryland, Baltimore, Maryland; and ³ Howard Hughes Medical Institute, Department of Cellular and Molecular Pharmacology, University of California, San Francisco, California

Requests for reprints: Silvia Montaner, Department of Oncology and Diagnostic Sciences, University of Maryland, 650 West Baltimore Street, 7th North, Room 7263, Baltimore, MD 21201. Phone: 410-706-7936; Fax: 410-706-0519; E-mail: smontaner{at}umaryland.edu.

Key Words: endothelial cell • Kaposi's sarcoma • rapamycin • sirolimus • PI-103 • mTOR • Akt • PI3 kinase • Kaposi's sarcoma–associated herpesvirus • KSHV • human herpesvirus-8 • HHV-8 • G protein–coupled receptor • vGPCR

Rapamycin (or sirolimus), the prototypical inhibitor of the mammalian target of rapamycin (mTOR) and an immunosuppressant used for the prevention of renal transplant rejection, has recently emerged as an effective treatment for Kaposi's sarcoma (KS), an enigmatic vascular tumor and a model for pathologic angiogenesis. Indeed, recent work supports a role for mTOR as a central player in the transformation of endothelial cells by the KS-associated herpesvirus–encoded G protein–coupled receptor (vGPCR), the viral oncogene believed to be responsible for causing KS. However, emerging evidence that rapamycin may transiently promote the activation of Akt may limit its use as an anti-KS therapy. Here, we show that activation of Akt in endothelial cells expressing vGPCR is augmented by treatment with rapamycin, resulting in the up-regulation of several Akt proliferative and survival pathways. However, use of a novel dual phosphatidylinositol 3-kinase (PI3K)/mTOR inhibitor, PI-103, effectively and independently blocked activation of both PI3K and mTOR in vGPCR-expressing endothelial cells. This resulted in more effective inhibition of endothelial cell proliferation and survival in vitro and tumor growth in vivo. Our results suggest that PI-103 may be an effective therapeutic option for the treatment of patients with KS. Moreover, as KS may serve as a model for pathologic angiogenesis, our results further provide the basis for the early assessment of PI-103 as an antiangiogenic chemotherapeutic. [Cancer Res 2008;68(20):8361–8]

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