# Using Nonclassical Estrogen Signaling to Prevent Melanoma

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $442,834

## Abstract

Project summary: Despite advances in melanoma treatment, only 33% of patients with advanced
disease respond to the most effective therapy and mean survival is only 23 months. Millions of people
with red hair, or light skin pigmentation have an especially high melanoma risk. Although strategies to
decrease this risk are lacking, our recent discoveries suggest that melanoma incidence may be
diminished by pharmacologically activating the G-Protein Estrogen Receptor (GPER), a protein on
melanocytes with activity completely distinct from the classic estrogen receptor (ERα/β). Although there
are no approved drugs that target GPER, GPER is activated in melanocytes by a selective synthetic
compound (G-1) that does not have any classic estrogen activity. We recently determined that
pharmacologic GPER activation in vivo inhibits established melanomas, largely by inducing terminal
differentiation in cancer cells. Our preliminary studies now suggest that G-1 mediated GPER activation
in melanocytes induces long-term epigenetic changes that prevent future melanoma, while allowing
skin melanocytes to continue to function normally.
 In Aim I we will use primary human melanocytes to determine the specific histone modifying enzymes
required for inducing epigenetic transcriptional memory that maintains a heightened state of cellular
differentiation after transient GPER activation, and test whether HDAC inhibition potentiates the
differentiation effects of the GPER agonist.
 In Aim II we will validate preliminary results suggesting that GPER signaling induces pathways that
promote DNA repair, and thereby minimizes the accumulation of DNA mutations after ultraviolet (UV)
exposure. We will determine the mechanism(s) downstream of GPER that mediate the improved DNA
damage response, which may help highlight additional therapeutic targets.
 In Aim III we will use both human and mouse melanoma models to directly test whether G-1
activation of GPER promotes DNA repair after UV exposure in vivo, and inhibits melanoma
development.

## Key facts

- **NIH application ID:** 9895651
- **Project number:** 5R01CA227188-02
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** TODD W RIDKY
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $442,834
- **Award type:** 5
- **Project period:** 2019-04-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9895651

## Citation

> US National Institutes of Health, RePORTER application 9895651, Using Nonclassical Estrogen Signaling to Prevent Melanoma (5R01CA227188-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9895651. Licensed CC0.

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