# Project 3: Molecular Targets of Rexinoid Action in Skin

> **NIH NIH P01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2021 · $157,804

## Abstract

PROJECT SUMMARY.
 The incidence of non-melanoma skin cancer is increasing worldwide and it is especially high in the solid
organ transplant population. These cancers are associated with a high morbidity in this population and, thus, it
represents a significant public health burden. Systemic retinoids have proven to be effective for the
chemoprophylaxis of non-melanoma skin cancers. They act by activating the transcription of RXR/RAR target
genes, but their exact cancer chemopreventive mechanism is still not clear because retinoids have pleiotropic
effects. The major limitation to the use of synthetic RAR agonists (acitretin, isotretinoin) at the doses required for
skin cancer prevention, is poor tolerance due to headaches, musculoskeletal symptoms, hyperlipidemia,
mucocutaneous inflammation and hepatotoxicity. The first clinically approved RXR agonist, bexarotene, is better
tolerated than retinoids. However, hyperlipidemia induced by oral bexarotene is a major problem.
 Drs. Muccio and Atigadda (Project 2 and Core 2) have designed a selective RXR agonist, UAB30, which
effectively prevents epithelial cancers (mammary, skin, etc.) but does not increase serum triglycerides in rodents
or humans. While UAB30 clearly shows promise as a safe and effective chemopreventive drug, its mechanism
of action at the molecular level is poorly understood. Our preliminary data indicate that treatment with UAB30
results in increased levels of ATRA in human skin epidermis. We propose that UAB30 potentiates the
transcriptional activity of existing endogenous ATRA mediated by RXR/RAR heterodimers, which induce
upregulation of genes responsible for the biosynthesis of ATRA. This leads to elevated levels of ATRA and
further increase in transcriptional activity of RXR/RAR heterodimers. We also propose that the amplitude of
upregulation of ATRA target genes serves as a good indicator of the potency of rexinoids for chemoprevention
of non-melanoma skin cancer. Finally, we propose that evaluation of the UAB30 analogs based on their ability
to induce ATRA signaling in epidermis can lead to development of the next generation of rexinoids with efficacy
comparable to bexarotene but without its toxicity. These hypotheses will be tested by defining the molecular
targets and studying the mechanism of action of UAB30 in epidermis using the dominant-negative mutant of
RXRα and metabolic assays of retinoid metabolism (Aim 1); by characterizing the effect of UAB30 on skin cancer
and markers of cell differentiation and proliferation using our novel model of human squamous cell carcinoma
and mouse models of squamous cell carcinoma and basal cell carcinoma developed by Dr. Athar (Core 3); and
by evaluating the next generation of UAB30 analogs for their potency in upregulation of ATRA target genes
relative to UAB30 and bexarotene (Aim 3). These studies will provide novel insights into the mechanism of
UAB30 action in epidermis, and are critical for developing the next generation of highly ...

## Key facts

- **NIH application ID:** 10263924
- **Project number:** 5P01CA210946-05
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Natalia Y Kedishvili
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $157,804
- **Award type:** 5
- **Project period:** 2017-09-01 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10263924

## Citation

> US National Institutes of Health, RePORTER application 10263924, Project 3: Molecular Targets of Rexinoid Action in Skin (5P01CA210946-05). Retrieved via AI Analytics 2026-06-12 from https://api.ai-analytics.org/grant/nih/10263924. Licensed CC0.

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