Abstract P3-05-08: Effect of a novel selective progesterone receptor modulator EC312 for menopausal hormone therapy (MHT) in comparison with Bazedoxifene in vitro
Authors: Nair Hareesh B , Santhamma Bindu , Elger Walter , Nickisch Klaus J 
Published: May 2015

Abstract
Significant increase in the breast cancer risk reported from the Women’s health initiative (WHI) study and other clinical studies in postmenopausal women lead to a significantly reduced usage of estrogen/ progestin based HRT treatment in women.
A new and interesting approach to provide women with an effective treatment for vasomotor symptoms without an increased breast cancer risk has been reported in preclinical and clinical studies. A combination of conjugated estrogens (CE) + selective estrogen receptor modulator (SERM), bazedoxifene (BZA) offers an effective treatment for overcoming vasomotor symptoms but preventing the proliferation of breast tissue. However, this treatment also has some drawbacks. A higher rate of induced endometrial hyperplasia due to unopposed estroginicity with BZA+ CE treatment regimen has been noted in recent randomized clinical trials. In addition, the risk of venous thromboembolic events has been shown not avoided completely in women who were older at the time of BZE+CE treatment compared with those who were younger. Therefore an unmet need for new HRT regiments that combine effective treatment of symptoms without increasing the risk of breast cancer in postmenopausal women.
A potential approach is the combination of estradiol with a partial agonistic antiproprgestin (mesoprogstin or SPRM). In order to test the hypothesis we have compared the combinatory effect of BZA with estrogen (E2) as well as a novel SPRM, EC312+ E2 in a cell culture model of postmenopausal breast cancer. In our model, we have found that the antiestrogenic effect of BZA on T47D cell growth was comparable that of EC312. Both EC312 and BZA increased apoptosis dose dependently in the presence of E2 as well as reduced E2 mediated BrdU incorporation as a read out of cell proliferation. E2 (1nM) treatment increased the expression of anti-apoptotic genes whereas 100nM treatment of EC312 and BZA decreased the levels of anti-apoptotic genes. Expression of E2 stimulated effect on target genes such as cMyc, pS2 and Cyclin D1 were reduced with the treatment of EC312 or BZA. It is evident from our study that EC312 as a novel SPRM exerted no agonistic effects on human breast cancer cells and effectively blocked the stimulatory actions of E2 or conjugated estrogens. The in vitro molecular characterization of EC312 was performed using gene transactivation assays and confirmation of EC312 as a PRM was determined in cycling guinea pig model. Our future animal model with breast cancer xenografts will underscore the possibility of using EC312 as a safer SPRM that antagonize the growth promotional effect of estrogens as well as eliminating the increased breast cancer risk of progestin component of MHT. Further rationale for choosing SPRM/mesoprogestin such as EC312 would stabilize the uterine tissue and endometrium to minimize the oligo-menorrhea and endometrial hyperplasia associated with MHT.
Citation Format: Hareesh B Nair, Bindu Santhamma, Walter Elger, Klaus J Nickisch. Effect of a novel selective progesterone receptor modulator EC312 for menopausal hormone therapy (MHT) in comparison with Bazedoxifene in vitro [abstract]. In: Proceedings of the Thirty-Seventh Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2014 Dec 9-13; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2015;75(9 Suppl):Abstract nr P3-05-08.