Pan-cancer analysis to identify a novel class of glucocorticoid and androgen receptor antagonists with potent anti-tumor activity.

Abstract

e15663 Background: Large public cancer databases have allowed identification of novel mechanisms of oncogenesis and development of pharmacotherapies targeting these pathways. Examples are the androgen receptor (AR) and glucocorticoid receptor (GR). The Cancer Genome Atlas (TCGA) shows these receptors to have significantly increased expression over matched, normal tissue in several cancer types including: glioblastoma (AR and GR tumor-to-tissue ratios: AR = 6.53, GR = 1.42), low-grade gliomas (AR = 5.08, GR = 1.8), kidney clear cell carcinoma (AR = 1.89, GR = 1.82), kidney papillary cell carcinoma (AR = 3.64, GR = 1.2), and pancreatic adenocarcinoma (AR = 3.77, GR = 3.31). Methods: To investigate the therapeutic potential of targeting these receptors, we produced a series of analogues from a known GR inhibitor that all have the ability to target both the GR and the AR. Of these, PT150 is a clinical stage small molecule and PT157 is a preclinical stage small molecule. We began investigating the potential of these compounds to inhibit tumor growth using the NIH 60 cell lines panel with follow up in vitro testing and validation in clinically derived samples and established cell lines, including some cancers not include in the NIH 60 cell line panel or TCGA. Results: NIH 60 panel disclosed sensitivity towards gliomas, pancreatic cancer, and prostate cancer. For brain tumors, we investigated the effects of these inhibitors on glioblastoma, meningioma, and brain metastases. One analogue in particular, PT157, was able to significantly reduce cell viability after three days in culture in a dose dependent manor for each of the three tumor types and do so at a dose that is safely achievable in humans. Dose-dependent effects of PT150 and PT157 were observed in both androgen dependent and independent prostate cell lines, reducing viability of LNCaP, 22RV1 and DU145 cells. Similar data were also achieved in an in vitro pancreatic cancer model. Using patient-derived, primary pancreatic ductal adenocarcinoma (PDAC) cells, we found that both PT150 and PT157 were effective as monotherapies, inducing cell death in a dose dependent manner. In addition, both PT150 and PT157 significantly increased nab-paclitaxel sensitivity in nab-paclitaxel-resistant isogenic PDAC cells. Based on these in vitro data, we have begun pre-clinical experiments using in vivo mouse models. Conclusions: Our work has identified previously undescribed mechanisms of oncogenesis in several cancer types, as well as an efficacious class of novel compounds with the potential to inhibit them.