This review focuses on our efforts to translate a low-toxicity
retinoid X receptor-selective agonist, UAB30, to the clinic for the prevention of breast
cancers. The review is divided into several sections. First, the current status of
breast cancer prevention is discussed. Next, preclinical studies are presented that support translation of rexinoids to the clinic for
cancer prevention. While current FDAapproved
retinoids and rexinoids demonstrate profound effects in treating
cancers, they lack sufficient safety for long term use in the high risk population that is otherwise disease free. The review stresses the need to identify
cancer preventive drugs that are effective and safe in order to gain wide use in the clinic. Due to the heterogeneity of the disease, UAB30 is evaluated for the prevention of ER-positive and ER-negative
mammary cancers. Since
selective estrogen receptor modulators and
aromatase inhibitors are used clinically to prevent and treat ER-positive breast
cancers, preclinical studies also must demonstrate efficacy of UAB30 in combination with existing drugs under use in the clinic. To support an
Investigational New Drug Application to the FDA, data on pharmacology and toxicity as well as mutagenicity is gathered prior to human trials. The review concludes with a discussion of the outcomes of human Phase 0/1 clinical trials that determine the safety and pharmacology of UAB30. These studies are essential before this agent is evaluated for efficacy in phase 2 trials. Success in phase 2 evaluation is critical before long-term and costly phase 3 trials are undertaken. The lack of surrogate
biomarkers as endpoints for phase 2 evaluation of rexinoid preventive agents is discussed.