# Project 2. Harnessing Epigenetic Regulation of Endogenous Retroelements in Melanoma

> **NIH NIH P50** · YALE UNIVERSITY · 2023 · $383,417

## Abstract

PROJECT 2: PROJECT SUMMARY
Despite remarkable progress in treating advanced melanoma, the prognosis remains variable. Specifically,
nearly all metastatic melanoma patients develop resistance to targeted therapy with time, while approximately
half do not respond to immunotherapy. These challenges highlight an urgent need to develop novel therapeutic
interventions, improve current treatments, and develop biomarkers that predict response. Emerging evidence
suggests that epigenetic regulators KDM5B and SETDB1 as therapeutic targets and endogenous retroelements
(REs) as biomarkers of response to immunotherapies. Our long-term goal is to translate our findings of novel
mechanisms involved in melanoma progression to the clinic. The objectives of this project are to dissect the
cellular mechanisms by which KDM5B and SETDB1 loss induce anti-tumor immunity, develop biomarkers to
predict response to immune checkpoint inhibitors, and to evaluate the therapeutic potential of depleting KDM5B
in melanoma. Our central hypotheses are that KDM5B and SETDB1 targeting de-repress the expression
of retroelements to initiate robust anti-melanoma immune responses, and retroelements can be
harnessed to predict response to immunotherapy. The hypothesis is supported by previous studies as well
as our own preliminary data from patient-derived melanomas and preclinical melanoma models. The rationale
is that better understanding of how KDM5B and SETDB1 suppress melanoma growth and anti-tumor immune
responses will result in new and innovative approaches to treat melanoma. The hypotheses will be tested in
three Specific Aims: 1) Dissect the mechanisms of immune responses induced by KDM5B and SETDB1 loss;
2) Evaluate the therapeutic potential of depleting KDM5B in melanoma; 3) Evaluate REs suppressed by KDM5B
and SETDB1 as predictive biomarkers in human melanoma. The proposed research is conceptually, technically,
and clinically innovative, because it aims to examine the therapeutic potential of KDM5B depletion using “first
in class” KDM5B degraders, and to evaluate RE levels as novel predictive biomarker for response to
immunotherapy. The results from these studies could impact the treatment of patients with melanoma and
increase our understanding of the factors that regulate anti-tumor immune responses.

## Key facts

- **NIH application ID:** 10711512
- **Project number:** 2P50CA121974-16
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** Qin Yan
- **Activity code:** P50 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $383,417
- **Award type:** 2
- **Project period:** 2006-06-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10711512

## Citation

> US National Institutes of Health, RePORTER application 10711512, Project 2. Harnessing Epigenetic Regulation of Endogenous Retroelements in Melanoma (2P50CA121974-16). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10711512. Licensed CC0.

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