Abstract P4-02-07: A Progesterone Receptor Modulator, CDB-4124, Inhibits Mammary Carcinogenesis by Suppressing Cell Proliferation In Vitro and In Vivo

Abstract

CDB-4124 (Proellex or Telapristone acetate) is a modulator of progesterone receptor (PR) signaling which has been employed in preclinical studies for the treatment of uterine fibroids and endometriosis. Here we provide evidence for its action in breast cancer from both in vitro and in vivo studies. When CDB-4124 is given to rats at 200 mg/kg for 24 months it prevents the development of spontaneous mammary hyperplastic and premalignant lesions. In a second set of experiments, we found that CDB-4124, given as subcutaneous pellets at two different dose suppressed MNU-induced mammary carcinogenesis in rats in a dose dependent manner (see table below). The high dose (30 mg over 84 days) increased tumor latency from 66 to 87 days (P<0.02), decreased incidence from 85% to 35% (P<0.01), and multiplicity, from 3.0 to 1.1 tumors/animal (P<0.01). Tumor burden (total of all tumor weights in an animal) decreased from 2.6 g to 0.26 g/animal (P<0.01). Moreover in suport of our observations, CDB-4124 significantly suppressed Ki-67 positive cells from 30.5±7.1% in placebo-treated to 25.4±14.4% in low-dose and further to 10.3±4.5% (P<0.001) in the high-dose treated animals. CDB-4124 increased latency and inhibited the incidence, multiplicity and burden of mammary tumors CDB-4124 inhibited cell proliferation and induced apoptosis in these mammary tumors and this correlated with decreased proportion of PR+ tumor cells. Serum progesterone was lowered but there were no effects on estradiol. This progesterone receptor modulator appears to exert its effects in the presence of estrogen. In a mechanistic study employing human T47D breast cancer cells we found that CDB-4124 suppressed G1/0-S transition by inhibiting cdk-2 and cdk-4 expression and this correlated with inhibition of ER expression. Taken together, these data indicates that CDB-4124 can suppress the development of spontaneous and carcinogen-induced ER+ mammary tumors in rats and thus newer progesterone receptor modulators may have implications for prevention and treatment of human breast cancer. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P4-02-07.