Cridanimod and progestin therapy in hormone-resistant endometrial cancer.

5597 Background: Cridanimod is a novel small molecule that has been shown to increase progesterone receptor (PR) expression in rat endometrium. We hypothesize that cridanimod, in combination with progestin therapy, will increase PR expression and, thus improve survival in a mouse model of advanced, high grade endometrial cancer. Methods: Hec50co cells, established in our laboratory to represent genetically and phenotypically type II endometrial cancer, were injected into the peritoneal cavity of 96 athymic mice. These mice were randomly divided into 6 groups, receiving the following therapies: control (no therapy), medroxyprogesterone acetate (MPA) alone, cridanimod 1mg IM twice a week plus MPA, cridanimod 3mg plus MPA, cridanimod 6mg plus MPA, and adenovirus-mediated PR expression plus MPA. PR expression in tumor tissue and serum interferon (IFN) levels were assayed via Western blot and ELISA, respectively. Results: Kaplan-Meier survival analysis showed that the group receiving MPA plus 6 mg cridanimod twice a week had a significantly longer survival time than the control or MPA alone (62 ± 7.0 days vs 38 ± 5 or 33 ± 3, respectively, p < 0.05). The group with MPA plus 3 mg cridanimod had a significantly longer survival than the group with MPA alone (56 ± 8.0 days vs 33 ± 3, p < 0.05). Western blot analysis showed that PR proteins were substantially higher in xenograft tumors from animals treated with cridanimod at doses of 3mg and 6mg when comparing to the control and MPA alone groups, ELISA data showed significant increases in IFNα and -β in cridanimod-treated mice in a dose-dependent manner. Conclusions: Combined progestin and cridanimod therapy significantly improved survival of mice with high-grade, advanced endometrial cancer. Cridanimod significantly increased PR expression, suggesting that the therapeutic benefit of combined therapy is mediated by up-regulation of PR, which is likely to be mediated through cridanimod induction of IFNα and IFNβ expression. Further investigation is warranted to determine the utility of this promising agent.