Abstract PD3-02: Second-generation selective glucocorticoid receptor modulators in triple-negative breast cancer
Authors: West DC , Hosfield DJ , Mayne CG , Skor MN , Styke SC , Pierce CF , Kocherginsky M , Hunt H , Fleming GF , Szmulewitz RZ , Tajkhorshid E , Greene GL , Conzen SD 
Published: May 2016

Triple-negative breast cancer (TNBC) lacks expression of the estrogen receptor (ER), progesterone receptor (PR), and HER2. A subset of primary TNBCs (at least 30%) expresses moderate to strong glucocorticoid receptor (GR) in greater than 10% of invasive tumor cells; in addition, we have reported that increased GR signaling promotes TNBC cell survival. Furthermore, our laboratory recently observed that patients with early stage/high-GR-expressing TNBCs have a relatively poor prognosis. Therefore, GR is being explored as a target for improving outcome in TNBC. Indeed, mifepristone, a well-characterized non-selective steroidal GR/PR antagonist, has shown promise in reversing GR-mediated tumor cell-survival signaling in TNBC. In vivo, increased TNBC xenograft chemosensitivity was observed when mifepristone was added to chemotherapy treatment. Most recently, a Phase I clinical trial demonstrated the safety and potential efficacy of mifepristone added to nab-paclitaxel chemotherapy in Stage IV TNBC patients.

Three highly selective non-steroidal GR antagonists (GRAs) have been investigated, CORT108297. CORT125134 (two aryl pyrazole-fused azadecalins) and CORT118335 (a pyrimidine dione). These new GRAs have 1) far less cross-reactivity than mifepristone with other nuclear receptor family members and 2) lower interaction profiles for drug metabolizing CYP enzymes. We hypothesized that selective GRAs would not only inhibit GR-induced pro-survival gene expression, but also increase TNBC chemosensitivity, and may eventually be a valuable adjunct therapy for treating chemotherapy-resistant TNBC.

To understand how GR modulators interact with the GR ligand-binding domain (LBD), we are employing two approaches: 1) computational modeling of the GRA-GR LBD based on published crystal structures of the GR LBD with mifepristone (in collaboration with UIUC), and 2) crystal structure analysis of the GR LBD with GR modulators. Preliminary computational results indicate that CORT108297 docks into the LBD and antagonizes GR activity by indirectly disordering Helix 12. Experiments are ongoing using various buffer conditions to produce crystals of the GR LBD with CORT108297 and CORT118335 for x-ray crystallography.

Secondly, we are functionally characterizing CORT108297, CORT125134, and CORT118335 for their ability to inhibit glucocorticoid induction of key GR-mediated target genes. Over the course of eight hours, we observed that the compounds exhibited temporal antagonism of the expression of GR target genes encoding anti-apoptotic proteins such as SGK-1, MCL-1, and MKP-1/DUSP1. Lastly, we are examining the selective GRAs' ability to enhance tumor cell cytotoxicity from paclitaxel in cell culture and in TNBC xenograft models. Preliminary results indicate that CORT125134 and CORT108297 significantly increase GR+ TNBC sensitivity to paclitaxel, and are well-tolerated in our in vivo models.

Citation Format: West DC, Hosfield DJ, Mayne CG, Skor MN, Styke SC, Pierce CF, Kocherginsky M, Hunt H, Fleming GF, Szmulewitz RZ, Tajkhorshid E, Greene GL, Conzen SD. Second-generation selective glucocorticoid receptor modulators in triple-negative breast cancer. [abstract]. In: Proceedings of the Thirty-Eighth Annual CTRC-AACR San Antonio Breast Cancer Symposium: 2015 Dec 8-12; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2016;76(4 Suppl):Abstract nr PD3-02.