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

Abstract

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 f84%. 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]

Magnetic resonance imaging for detection and determination of tumor volume in a genetically engineered mouse model of ovarian cancer

“…Longitudinal MRI was also used to accurately measure ovarian tumor size and response to treatment with RAD001 (Everolimus) showing that tumor onset and progression was significantly delayed in treated versus control mice. 23 Taken together, our results suggest that TgMISIIR-TAg-DR26 transgenic mice may be a useful model for the preclinical evaluation of novel combination therapies for the treatment of EOC.…”

“…We conducted a preclinical study of the therapeutic efficacy of RAD001 (Everolimus) in TgMISIIR-TAg-DR26 mice and showed that this single agent significantly delays tumor onset and progression in the mice. 23 The availability of reliable and accurate methods for in vivo imaging of normal ovaries and ovarian tumors provides the opportunity to fully characterize tumor growth kinetics, disease progression and therapeutic response. These analyses provide the information necessary to optimize preclinical studies so they can be conducted using fewer mice and longitudinal quantitative data is obtained for each mouse.…”

Rapamycin Extends Maximal Lifespan in Cancer-Prone Mice

“…[25][26][27][28][29] In particular, five MMTV-c-Neu mice bearing tumors were treated with 150 g rapamycin (a dose approximately 3 times higher than the dose used in our study) for 32 days and tumor regression was observed. 29 However, the effect of rapamycin on longevity of cancer-prone mice has not been previously investigated.…”

Cyclooxygenases expression and distribution in the normal ovary and their role in ovarian cancer in the domestic hen (Gallus domesticus)

“…The disease in hens appears to closely resemble the human disease, which in humans is correlated with ovulation frequency [6]. Whereas there are important rodent models for epithelial ovarian cancer, none of these ovarian carcinomas are linked to ovulation [7][8][9][10][11][12][13]. One of the most prevalent theories about the etiology of ovarian cancer is the "incessant ovulation hypothesis" first proposed by Fathalla [14].…”