Sensitization of neuroendocrine prostate cancer by RRx-001.

Abstract

280 Background: RRx-001 is a first-in-class dinitroazetidine nontoxic anticancer agent. Its actions include upregulation of oxidative stress, depletion of GSH and NADPH, anti-angiogenesis, epigenetic modulation and induction of viral mimicry. In a phase II clinical study (NCT02489903), RRx-001 reversed resistance to reintroduced platinum doublets in small cell lung cancer (SCLC) and other tumor types. RRx001 demonstrated clinical activity with a complete metabolic response of metastatic castration-resistant neuroendocrine prostate cancer (NEPC) after treatment with RRx-001 and reintroduced platinum doublets. Here, we used a preclinical model to further investigate RRx-001 sensitization of NEPC to platinum therapy. Methods: NCI-H660 spheroids were pre-treated with 1 mM RRx-001 or vehicle prior to treatment with carboplatin or docetaxel and cell proliferation was assessed. Cells were also pre-treated with both 1 mM RRx-001 and 10 mM N-acetyl cysteine (NAC) or 1 mM Buthionine-S,R-sulfoximine (BSO) to investigate the role of reactive oxygen species (ROS) in RRx-001 activity. NCI-H660 xenografts were pre-treated with RRx-001 (mimicking clinical activity) or vehicle prior to treatment with carboplatin, and tumor volume and body weight were monitored. Results: RRx-001 pre-treatment significantly decreased the IC50 of carboplatin from ~86 mM to 36 mM in vitro, whereas no significant effect was observed on the IC50 of docetaxel. The ROS inhibitor NAC reversed > 70% of RRx-001 sensitization to carboplatin, while co-pre-treatment with the ROS generator BSO significantly enhanced RRx-001 activity. In vivo, pre-treatment with RRx-001 prior to carboplatin significantly decreased tumor volume compared to vehicle, with ~50% greater reduction in mean tumor volume at 30 days. Body weight was not affected by RRx-001. Conclusions: This preclinical study supports the concept that “priming” with RRx-001 may be an effective therapeutic strategy to resensitize NEPC to initially highly effective platinum doublets. A phase 3 trial is planned, and studies with additional preclinical NEPC models will identify the mechanism of action of RRx-001.