This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Mabuchi, S. Articles by Testa, J. R. Search for Related Content PubMed PubMed Citation Articles by Mabuchi, S. Articles by Testa, J. R.

RAD001 (Everolimus) Delays Tumor Onset and Progression in a Transgenic Mouse Model of Ovarian Cancer

¹ Human Genetics Program, ² Ovarian Cancer Program, ³ Department of Pathology, ⁴ Biostatistics Facility, and ⁵ Spectroscopy Support Facility, Fox Chase Cancer Center, Philadelphia, Pennsylvania

Requests for reprints: Joseph R. Testa, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, PA 19111. Phone: 215-728-2610; Fax: 215-214-1623; E-mail: Joseph.Testa{at}fccc.edu.

The mammalian target of rapamycin (mTOR) is thought to play a critical role in regulating cell growth, cell cycle progression, and tumorigenesis. Because the AKT-mTOR pathway is frequently hyperactivated in ovarian cancer, we hypothesized that the mTOR inhibitor RAD001 (Everolimus) would inhibit ovarian tumorigenesis in transgenic mice that spontaneously develop ovarian carcinomas. We used TgMISIIR-TAg transgenic mice, which develop bilateral ovarian serous adenocarcinomas accompanied by ascites and peritoneal dissemination. Fifty-eight female TgMISIIR-TAg mice were treated with 5 mg/kg RAD001 or placebo twice weekly from 5 to 20 weeks of age. To monitor tumor development, mice were examined biweekly using magnetic resonance microimaging. In vivo effects of RAD001 on Akt-mTOR signaling, tumor cell proliferation, and blood vessel area were analyzed by immunohistochemistry and Western blot analysis. RAD001 treatment markedly delayed tumor development. Tumor burden was reduced by 84%. In addition, ascites formation, together with peritoneal dissemination, was detected in only 21% of RAD001-treated mice compared with 74% in placebo-treated animals. Approximately 30% of RAD001-treated mice developed early ovarian carcinoma confined within the ovary, whereas all placebo-treated mice developed advanced ovarian carcinoma. Treatment with RAD001 diminished the expression of vascular endothelial growth factor in tumor-derived cell lines and inhibited angiogenesis in vivo. RAD001 also attenuated the expression of matrix metalloproteinase-2 and inhibited the invasiveness of tumor-derived cells. Taken together, these preclinical findings suggest that mTOR inhibition, alone or in combination with other molecularly targeted drugs, could represent a promising chemopreventive strategy in women at high familial risk of ovarian cancer. [Cancer Res 2007;67(6):2408–13]

This article has been cited by other articles:

				I. Okamoto, T. Doi, A. Ohtsu, M. Miyazaki, A. Tsuya, K. Kurei, K. Kobayashi, and K. Nakagawa Phase I Clinical and Pharmacokinetic Study of RAD001 (Everolimus) Administered Daily to Japanese Patients with Advanced Solid Tumors Jpn. J. Clin. Oncol., September 25, 2009; (2009) hyp120v1. [Abstract] [Full Text] [PDF]

				Effects of Oral Contraceptives or a Gonadotropin-Releasing Hormone Agonist on Ovarian Carcinogenesis in Genetically Engineered Mice Cancer Prevention Research, September 1, 2009; 2(9): 792 - 799.

				S. Mabuchi, C. Kawase, D. A. Altomare, K. Morishige, K. Sawada, M. Hayashi, M. Tsujimoto, M. Yamoto, A. J. Klein-Szanto, R. J. Schilder, et al. mTOR Is a Promising Therapeutic Target Both in Cisplatin-Sensitive and Cisplatin-Resistant Clear Cell Carcinoma of the Ovary Clin. Cancer Res., September 1, 2009; 15(17): 5404 - 5413. [Abstract] [Full Text] [PDF]

				N. Zhang, S. Lyons, E. Lim, and P. Lassota A Spontaneous Acinar Cell Carcinoma Model for Monitoring Progression of Pancreatic Lesions and Response to Treatment Through Noninvasive Bioluminescence Imaging Clin. Cancer Res., August 1, 2009; 15(15): 4915 - 4924. [Abstract] [Full Text] [PDF]

				R. Crazzolara, A. Cisterne, M. Thien, J. Hewson, R. Baraz, K. F. Bradstock, and L. J. Bendall Potentiating effects of RAD001 (Everolimus) on vincristine therapy in childhood acute lymphoblastic leukemia Blood, April 2, 2009; 113(14): 3297 - 3306. [Abstract] [Full Text] [PDF]

				H. A. Lane, J. M. Wood, P. M.J. McSheehy, P. R. Allegrini, A. Boulay, J. Brueggen, A. Littlewood-Evans, S.-M. Maira, G. Martiny-Baron, C. R. Schnell, et al. mTOR Inhibitor RAD001 (Everolimus) Has Antiangiogenic/Vascular Properties Distinct from a VEGFR Tyrosine Kinase Inhibitor Clin. Cancer Res., March 1, 2009; 15(5): 1612 - 1622. [Abstract] [Full Text] [PDF]

				S. Mabuchi, Y. Terai, K. Morishige, A. Tanabe-Kimura, H. Sasaki, M. Kanemura, S. Tsunetoh, Y. Tanaka, M. Sakata, R. A. Burger, et al. Maintenance Treatment with Bevacizumab Prolongs Survival in an In vivo Ovarian Cancer Model Clin. Cancer Res., December 1, 2008; 14(23): 7781 - 7789. [Abstract] [Full Text] [PDF]

				C. R. Schnell, F. Stauffer, P. R. Allegrini, T. O'Reilly, P. M.J. McSheehy, C. Dartois, M. Stumm, R. Cozens, A. Littlewood-Evans, C. Garcia-Echeverria, et al. Effects of the Dual Phosphatidylinositol 3-Kinase/Mammalian Target of Rapamycin Inhibitor NVP-BEZ235 on the Tumor Vasculature: Implications for Clinical Imaging Cancer Res., August 15, 2008; 68(16): 6598 - 6607. [Abstract] [Full Text] [PDF]

				S. Mabuchi, D. A. Altomare, M. Cheung, L. Zhang, P. I. Poulikakos, H. H. Hensley, R. J. Schilder, R. F. Ozols, and J. R. Testa RAD001 Inhibits Human Ovarian Cancer Cell Proliferation, Enhances Cisplatin-Induced Apoptosis, and Prolongs Survival in an Ovarian Cancer Model Clin. Cancer Res., July 15, 2007; 13(14): 4261 - 4270. [Abstract] [Full Text] [PDF]