Translation of a Tissue-Selective Rexinoid, UAB30, to the Clinic for Breast Cancer Prevention

Publisher: Bentham Science Publishers

E-ISSN: 1873-4294|17|6|676-695

ISSN: 1568-0266

Source: Current Topics in Medicinal Chemistry, Vol.17, Iss.6, 2017-01, pp. : 676-695

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Abstract

This review focuses on our efforts to translate a low-toxicity retinoid X receptor-selectiveagonist, UAB30, to the clinic for the prevention of breast cancers. The review is divided into severalsections. First, the current status of breast cancer prevention is discussed. Next, preclinical studies arepresented that support translation of rexinoids to the clinic for cancer prevention. While current FDAapprovedretinoids and rexinoids demonstrate profound effects in treating cancers, they lack sufficientsafety for long term use in the high risk population that is otherwise disease free. The review stressesthe need to identify cancer preventive drugs that are effective and safe in order to gain wide use in theclinic. Due to the heterogeneity of the disease, UAB30 is evaluated for the prevention of ER-positiveand ER-negative mammary cancers. Since selective estrogen receptor modulators and aromatase inhibitorsare used clinically to prevent and treat ER-positive breast cancers, preclinical studies alsomust demonstrate efficacy of UAB30 in combination with existing drugs under use in the clinic. Tosupport an Investigational New Drug Application to the FDA, data on pharmacology and toxicity aswell as mutagenicity is gathered prior to human trials. The review concludes with a discussion of theoutcomes 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 inphase 2 evaluation is critical before long-term and costly phase 3 trials are undertaken. The lack ofsurrogate biomarkers as endpoints for phase 2 evaluation of rexinoid preventive agents is discussed.