Abstract C135: AZ’4425 is a potent, selective, and orally bio-available progesterone receptor antagonist that has shown anti-tumor activity and inhibition of cancer stem cell proliferation.

Abstract

Abstract Progesterone is an important hormone in breast cancer; the paracrine mediator of the progesterone receptor, RANKL plays a critical role in cancer stem cells, metastasis and tumorigenesis. Steroidal inhibitors of PR have shown modest clinical activity but have been limited by toxicity. AZ’4425 is a novel, potent non-steroidal progesterone receptor (PR) antagonist which selectively inhibits PR compared to other steroid hormone receptors (∼ 1000-fold ER, MR, GR, AR). AZ’4425 competitively inhibits progesterone binding, thus preventing progesterone-induced phosphorylation of PR, nuclear translocation and PR-induced transcription with an IC50 of 26nM. Anchorage independent growth of T47D cells is similarly inhibited with an IC50 of 25nM. Using cancer stem cell (CSC) assays (mammosphere formation and ALDH positivity) we have shown broad cellular activity in both ER/PR positive tumor cell lines and early and late stage clinical samples. Furthermore, AZ’4425 prevents the increase in CSCs, and miRNA changes (miR221/2 and miR200c) induced by anti-estrogen therapies, suggesting a potential role in prevention of acquired resistance. In vivo, the PR antagonist inhibits transcription of progesterone-induced genes including RANKL and SGK1. Notably, AZ’4425 results in significant inhibition of new tumor formation and results in stasis and regression of DMBA-induced tumors, both as monotherapy and in combination with letrozole. Citation Information: Mol Cancer Ther 2013;12(11 Suppl):C135. Citation Format: Christine M. Chresta, Denis Alferez, Georgia Cerillo, Emma Still, Adina Hughes, Graeme Walker, Jane Kendrew, Claire Sadler, Jayne Harris, Iain Simpson, Andrew P. Thomas, Al Rabow, Robert Clarke, Sacha Howell, Graham Richmond. AZ’4425 is a potent, selective, and orally bio-available progesterone receptor antagonist that has shown anti-tumor activity and inhibition of cancer stem cell proliferation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2013 Oct 19-23; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2013;12(11 Suppl):Abstract nr C135.