Abstract A63: Tamoxifen effectively suppresses both initiation of intraperitoneal tumors and established ovarian cancer growth in a fluorescent xenograft model

Abstract

Abstract Background: Sixty percent of serous ovarian carcinomas express the estrogen receptor (ER). The antiestrogen (AE) Tamoxifen and aromatase inhibitors (AI) are common therapies for chemoprevention and treatment of ER+ breast cancers, but have not been routinely employed in ovarian cancer. We propose that AE and AI will prevent the initial growth of intraperitoneal (IP) ovarian cancer implants and decrease the volume of established IP implants in a previously established fluorescent mouse xenograft model. Methods: PEO4 cells were rendered permanently fluorescent with a ZsGreen protein lentivirus. Ovariectomized athymic nude mice (NCI) received IP injections of 107 ER+ PEO4 ovarian cancer cells under an approved animal protocol. Subcutaneous implants of control cellulose (C) , 17 β-estradiol (E), tamoxifen (TAM), anastozole (AN), letrozole (LT) or combinations of drugs [E+TAM, E to TAM, AN +E, AN+TAM] (Sigma) were implanted at the time of IP injections. For experimental arms requiring a second surgery to remove or switch a pellet, disease was allowed to grow for 7 weeks, and then estrogen pellets were removed for estrogen withdrawal (EWD) or removed and substituted with tamoxifen (E to TAM) for an additional 7 weeks. Disease growth was monitored biweekly until 14 weeks by Xenogen IVIS fluorescent imaging, converted to photon flux units, and analyzed using GraphPad software. Uterine weights at necropsy were recorded as an assessment of estrogenic potency. Presence of disease detected by IVIS imaging was confirmed at necropsy. Results: E promoted growth of IP ER+ PEO4 cells significantly (p<0.05) more than C. EWD for 7 weeks significantly (p<0.05) decreased the volume of IP disease to control baseline. Continuous TAM suppression was not significantly different than C, indicating that the mixed agonist/antagonist TAM is working as an antiestrogen when alone. Substitution of TAM for E after 7 weeks of unopposed E decreased IP disease, while continuous E+TAM for 14 weeks was not different than E alone, indicating that E stimulation predominates. Anastozole alone and letrozole alone did not suppress disease beyond C. AN and LT in combination with E were not effective inhibitors of E stimulation. E+TAM stimulated more disease than AN+TAM indicating that TAM is estrogenic only in the presence of E. The combination of an AE and AI was not more effective than AE alone. Conclusions: The mixed agonist/antagonist tamoxifen acts as an antagonist when alone, but an agonist in the presence of estrogen in an IP model of ovarian cancer. Antiestrogens such as tamoxifen may be effective adjuvant therapy after removal of endogenous ovarian estrogen in ovarian cancer. Continuous tamoxifen could be investigated as a maintenance therapy after initial ovarian cancer remission through surgery and chemotherapy. Citation Format: Douglas Hicks, Nicole Manning, Monique A. Spillman. Tamoxifen effectively suppresses both initiation of intraperitoneal tumors and established ovarian cancer growth in a fluorescent xenograft model. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr A63.