Targeting the RXR Pathway for the Prevention of Triple Negative Breast Cancer

Breast cancer remains a significant health problem in women. Chemoprevention of breast cancer is the most effective way of reducing breast cancer deaths in high risk populations. Studies using selective estrogen receptor (ER)modulators (SERMs), and aromatase inhibitors, have shown that breast cancer prevention is feasible; however, these drugs do not prevent ER-negative tumors and are often not used due to concerns about their toxicity. Importantly, ER-negative breast cancer represents 30 to 40% of breast cancer cases in the United States, and many of these ER-negative cancers are “triple-negative” (lacking ER, progesterone receptor (PR), and HER2 (or ErbB2) expression). These triple-negative breast cancers (TNBC), which occur at highest frequency in young and African American women, are highly aggressive and have extremely poor prognoses even when treated with highly toxic chemotherapy. The most commonly mutated gene in TNBCs is the p53 gene, which is mutated in 80% or more of these tumors. TNBC tumors also frequently have BRCA1 gene mutations, especially in women with a family history of breast cancer. Evidently, there is a clear need for the clinical development of new agents with novel mechanisms of action, documented/established efficacy and minimal toxicity for the prevention of ER negative and Triple negative breast cancers. Studies have shown that retinoid X receptor (RXR)-specific ligands (rexinoids) can prevent ER-positive and ER-negative tumors in rodents. Although some studies demonstrated that retinoids and RXR-selective retinoids or “rexinoids” prevent mammary tumors in animal models, these agents are known to have toxicity in humans. RXR agonists such as LG100268 and bexarotene have been extensively studied and have shown to suppress breast tumor development in transgenic mice. Toxicities like hyperlipidemia, hepatotoxicity, and lack of selectivity towards RXR are hindrance for these agents moving to clinic. Studies showed that the synthetic rexinoid 9-cis-UAB30 prevents mammary tumors in carcinogen-treated rats, in a genetic mouse model (MMTV-Neu) of ER− breast cancer and is also being tested in early clinical trials (NCT00896974, NCT01336387, NCT01935960, NCT02876640). IRX-4204 is a potent, selective, oral agonist of the RXR pathways. IRX-4204 binds with very high affinity and selectivity to the RXRs. IRX-4204 has very limited affinity for the Retinoic Acid Receptors (RAR). In functional transactivation assays, IRX4204 was more potent in activating RXR homodimers than RAR-RXR heterodimers, and IRX4204 does not activate other heterodimers such as RXR-PPAR, RXR-LXR, and RXR-FXR. This selectivity may confer increased safety of IRX-4204. IRX-4204 has been studied in four clinical trials, a completed phase 1 for treatment of early Parkinson’s Disease (NCT02438215); a phase 1 study in patients with refractory malignancies (terminated); a phase 1 study in non-small cell lung cancer (NCT00964132); and a completed phase 2 trial in taxane refractory prostate cancer (NCT01540071). Liby et al. showed the cancer preventive activity of IRX 4204 in a preclinical ER−breast cancer model. The overarching goal of this task order is to evaluate chemopreventive efficacy of IRX-4204 in a preclinical model of BRCA1 driven triple-negative breast cancer.