Translation of a Tissue-Selective Rexinoid, UAB30, to the Clinic for Breast Cancer Prevention
Donald D Muccio1, Venkatram R Atigadda, Wayne J Brouillette
1901 14th street south, Birmingham Al 35294, United States.
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.
Insights
This review details the development of UAB30, a selective retinoid X receptor agonist, for breast cancer prevention. Early clinical trials show UAB30 is safe and well-tolerated, supporting further investigation for this crucial application.
Area of Science:
- Oncology
- Pharmacology
- Drug Development
Background:
- Current breast cancer prevention strategies have limitations in safety and efficacy for long-term use.
- Retinoids and rexinoids show promise but require improved safety profiles for preventative applications.
- There is a critical need for effective and safe cancer preventive agents.
Purpose of the Study:
- To review the translation of UAB30, a low-toxicity retinoid X receptor-selective agonist, for breast cancer prevention.
- To evaluate UAB30's efficacy in preclinical models for both ER-positive and ER-negative breast cancers.
- To discuss the safety, pharmacology, and clinical trial outcomes of UAB30.
Main Methods:
- Preclinical studies assessing UAB30's efficacy and safety in breast cancer models.
- Evaluation of UAB30 in combination with existing breast cancer therapies.
- Analysis of data supporting an Investigational New Drug Application, including pharmacology, toxicity, and mutagenicity.
- Review of Phase 0/1 human clinical trial outcomes for safety and pharmacology.
Main Results:
- UAB30 demonstrates potential for breast cancer prevention in preclinical studies.
- Phase 0/1 clinical trials indicate UAB30 is safe and has a favorable pharmacology.
- Data supports the progression of UAB30 towards Phase 2 efficacy trials.
Conclusions:
- UAB30 is a promising candidate for breast cancer prevention due to its selective mechanism and favorable safety profile.
- Further clinical evaluation in Phase 2 trials is warranted to establish efficacy.
- Development of surrogate biomarkers is crucial for efficient evaluation of rexinoid preventive agents.
