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THE MAMMALIAN TARGET OF RAPAMYCIN (MTOR) AS A TARGET FOR CANCER CHEMOTHERAPY James J. Gibbons, Jr.*, L. Toral-Barza, W-G Zhang, P. Frost, J. Skotnicki, C. Gaydos, J. Lucas and K. Yu Wyeth Research, 401 N. Middletown Rd., Pearl River, NY 10965 *[email protected] The mammalian target of rapamycin (mTOR) was originally identified in yeast as the protein responsible for mediating the anti-fungal activity of rapamycin1, a natural product originally isolated and characterized at Wyeth in 19752. Rapamycin has been a critical reagent in the elucidation of cell signaling pathways regulated by mTOR. The work of many investigators has established that mTOR regulates cell size and proliferation in part through control of protein synthesis of a subset of cell cycle regulatory proteins3,4. In yeast, TOR activity is regulated by nutrient availability and in mammalian cells mTOR appears to integrate signals from both nutrient and growth factor pathways. Inasmuch as human oncogenes and tumor suppressor genes are often components of growth factor signaling pathways, mTOR is a potential target for anti-cancer chemotherapy. We have studied the effects of mTOR inhibition by the rapamycin ester CCI-779 (Temsirolimus) in preclinical models of breast, prostate, glioblastoma, and renal cell carcinoma. In breast cancer models responsiveness to mTOR inhibition correlated with activation of the PI3K pathway either through growth factor dependence (estradiol), mutation of growth factor receptor (her2/neu), or loss of the tumor suppressor gene PTEN.5 Cells resistant to the mTOR inhibitor were rendered sensitive by stable transfection of activated Akt (myristoylated) or by knockout of the PTEN gene using a cre-lox system. PTEN-/- lines across several tissue types were invariably sensitive to CCI-7796,7 whereas PTEN+/+ lines were either sensitive or insensitive. Sensitive lines tended to show evidence of Akt activation. 1 In a screening assay employing PTEN-/- cells, we identified non-rapamycin like compounds that selectively inhibited proliferation of PTEN-/- cells. Preliminary characterization of these compounds suggest they partially inhibit mTOR through modulation of an Akt regulated target TSC2. Taken together, these data suggest that persistent activation of Akt confers sensitivity to mTOR inhibitors. The effect of mTOR inhibition on protein expression is not restricted to cell cycle proteins8. In a human renal cell carcinoma model deficient for the Von Hippel Lindau (VHL) tumor suppressor gene, CCI-779 inhibited production of the hypoxia inducible transcription factor HIF-2α. Expression of HIF-2α regulated genes such as vascular endothelial cell growth factor (VEGF) were also suppressed by the mTOR inhibitor. In addition, proangiogenic cytokines such as IL-8 and IL-6 were down regulated by CCI-779 by an as yet undefined mechanism. These data prompted us to study the effect of CCI-779 in combination with other anti-angiogenic agents. The combination of interferon-α with CCI-779 in renal cell carcinoma xenografts synergistically inhibited tumor growth despite showing little evidence of even additivity on cell proliferation in vitro. These data suggest an anti-angiogenic effect of mTOR inhibition in this renal cancer model. mTOR inhibition by CCI-779 (Temsirolimus) in clinical trials has shown objective responses in renal cell and breast carcinoma and mantle cell lymphoma. Preclinical studies suggest the potential for direct anti-proliferative and antiangiogenic activity through mTOR inhibition. Inasmuch as the tendency in the clinic of some tumor types to respond to mTOR inhibition with a stable disease phenotype (renal, breast) and others with significant objective responses (mantle cell lymphoma), the anti-tumor effector molecules downstream of mTOR may depend on cell context and may differ amongst tumor types. Identification of mTOR regulated anti-tumor targets will be essential to optimize the single agent activity of mTOR inhibitors and to optimize combination therapies employing mTOR inhibitors. 2 REFERENCES 1. Heitman J, Movva NR, and Hall MN. Targets for cell cycle arrest by the immuno-suppressant rapamycin in yeast. Science 53:905, 1991. 2. Vezina C, Kudelski A, and Sehgal SN. Rapamycin (AY-22, 989), a new anti-fungal antibiotic. I. Taxanomy of the producing streptomycete and isolation of the active principle. J Antibiot (Tokyo) 10:721, 1975. 3. Schmegle T and Hall MN. TOR, a central controller of cell growth. Cell 103:193, 2000. 4. Hay N and Sonenberg N. Upsteam and downstream of mTOR. Genes Dev 18:1926, 2004. 5. Yu K, Toral-Barza L, Discafani C, Zhang WG, Skotnicki J, Frost P, and Gibbons JJ. mTOR, a novel target in breast cancer: the effect of CCI-779, an mTOR inhibitor, in preclinical models of breast cancer. Endoci Relat Cancer 8:249, 2001. 6. Neshat MS, Mellinghoff IK, Tran C, Stiles B, Thomas G, Petersen R, Frost P, Gibbons JJ, Wu H, and Sawyers CL. Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR. PNAS 98:103, 2001. 7. Podsypanina K, Lee RT, Politis C, Hennessy I, Crane A, Puc J, Neshat M, Wang H, Yeng L, Gibbons JJ, Frost P, Dreisbeck V, Blenis J, Gaciong Z, Fisher P, Sawyers C, Hendrick-Ellenson L, and Parsens, R. An inhibition of mTOR reduces neoplasia and normalizes P70/S6 kinase activity in PTEN +/- mice. PNAS 98:10320, 2001. 8. Laughner E, Taghari P, Chiles K, Mahon PC, and Semenza GL. Her2 (neu) signaling increases the rate of hypoxia-inducible factor 1α (HIF-1α) synthesis: a novel mechanism for HIF-1 mediated vascular endothelial growth factor expression. Mol Cell Biol 21:3995, 2001. 3