Abstract 5061: TET inhibits prostate cancer tumor growth, progression and metastasis in TRAMP mice

Abstract

Abstract Introduction: Prostate cancer (PCa) is the 2nd most common malignancy in USA. Novel agents for treatment of advanced PCa are warranted. Transgenic adenocarcinoma of the mouse prostate (TRAMP) is an autochthonous mouse model exhibits both histological and morphological features that mimic human prostate carcinogenesis. Herein, for the first time, we evaluated the in vivo effects of TET, a derivative of Tetrandrine in TRAMP model. Methods: Beginning 12 weeks of age, male TRAMP mice were administrated with TET (30 mgm/kg body weight, orally, alternative days) in PBS or PBS alone (Control) till 30 weeks of age. Body weight (B) of animals was recorded weekly. At various time points animals were euthanized, genitourinary tract (G) were weighed. Prostate tissue was subjected to immunohistochemical analyses for SV40-TAg, epithelial-mesenchymal transition (EMT), proliferation, neuroendocrine differentiation (NED) and apoptosis. Multiple organs were examined for drug toxicity and lungs were analyzed for metastasis. Results: TRAMP mice exhibit to high-grade prostatic intraepithelial neoplasia (PIN) by 12 weeks and progresses to poorly differentiated adeno-carcinoma by 30 weeks with distant metastasis to lungs. TET feeding did not show any considerable difference body weight loss profiles during the entire treatment regimen. At the time of necropsy, there was no evidence of edema, abnormal organ size or appearance in non-target organs. TET gavage group showed (p<0.005) lower G/B ratio compared to the PBS treated group. These findings clearly indicate that TET dosing is non-toxic and restricts the abnormal growth of the prostate in TRAMP mice. TET repress the EMT as well as NED transition and inhibits cell proliferation (p<0.005) by Ki-67 staining. Oral administration of TET inhibits PCa growth and progression by increases (p<0.005) apoptosis in tumor tissues. Further, TET inhibited metastasis as there was significant (p<0.005) decrease in metastasis to lungs in TET treated animals. Conclusion: Human achievable dose of TET treatment to TRAMP mice bearing prostate tumor, exhibited no-observed-adverse-effect-level in toxicology evaluations and also significantly inhibited tumor growth, progression, local invasion and distant metastasis involving suppression of tumor, and thus could have potential against human PCa. Citation Format: Hari K. Koul, Prakash Srinivasan Timiri Shanmugam, Praveen K. Jaiswal, Sweaty Koul. TET inhibits prostate cancer tumor growth, progression and metastasis in TRAMP mice [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5061. doi:10.1158/1538-7445.AM2017-5061