Title:Translation of a Tissue-Selective Rexinoid, UAB30, to the Clinic for Breast Cancer Prevention
Volume: 17
Issue: 6
Author(s): Donald D. Muccio, Venkatram R. Atigadda, Wayne J. Brouillette, Kirby I. Bland, Helen Krontiras and Clinton J. Grubbs
Affiliation:
Keywords:
RXR, Tissue selective rexinoids, UAB30, Breast cancer, Rexinoids, Chemoprevention.
Abstract: 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.
