vt-464 and Triple-Negative-Breast-Neoplasms

Increased rates of locoregional recurrence (LR) have been observed in triple negative breast cancer (TNBC) despite multimodality therapy, including radiation (RT). Recent data suggest inhibiting the androgen receptor (AR) may be an effective radiosensitizing strategy, and AR is expressed in 15-35% of TNBC tumors. The aim of this study was to determine whether seviteronel (INO-464), a novel CYP17 lyase inhibitor and AR antagonist, is able to radiosensitize AR-positive (AR+) TNBC models. In cell viability assays, seviteronel and enzalutamide exhibited limited effect as a single agent (IC50 > 10 μM). Using clonogenic survival assays, however, AR knockdown and AR inhibition with seviteronel were effective at radiosensitizing cells with radiation enhancement ratios of 1.20-1.89 in models of TNBC with high AR expression. AR-negative (AR-) models, regardless of their estrogen receptor expression, were not radiosensitized with seviteronel treatment at concentrations up to 5 μM. Radiosensitization of AR+ TNBC models was at least partially dependent on impaired dsDNA break repair with significant delays in repair at 6, 16, and 24 h as measured by immunofluorescent staining of γH2AX foci. Similar effects were observed in an

Topics: Androgen Receptor Antagonists; Animals; Antineoplastic Combined Chemotherapy Protocols; Benzamides; Cell Line, Tumor; Enzyme Inhibitors; Female; Humans; Lyases; MCF-7 Cells; Mice; Mice, Inbred C57BL; Mice, SCID; Naphthalenes; Nitriles; Phenylthiohydantoin; Radiation Tolerance; Radiation-Sensitizing Agents; Receptors, Androgen; Steroid 17-alpha-Hydroxylase; Triazoles; Triple Negative Breast Neoplasms; Xenograft Model Antitumor Assays