# Metabolic and epigenetic dependencies in melanomas during metastasis and targeted-drug resistance

> **NIH NIH R01** · DANA-FARBER CANCER INST · 2022 · $307,356

## Abstract

Project Summary
Metastatic melanoma was until recently considered an untreatable disease, but the discovery of small
molecules that inhibit oncogenic BRAF(V600E) and approaches that unleash the immune system against
tumors have brought hope to melanoma patients. Not every patient will have meaningful therapeutic benefit
from these treatments and durable disease remission remains elusive for most. Among the causes of the
failure to respond or early relapse is a dynamic cancer cell heterogeneity that facilitates outgrowth of therapy
resistant tumors with enhanced malignancy traits. In order to extend the use of current therapies, we propose
to identify alternative molecular targets that could be harnessed for combinatorial treatment exploit and might
hold promise for sustainable therapeutic benefit. Specifically, whether metabolic and epigenetic processes
provide collateral dependencies within highly metastatic and chronic BRAF-targeted drug-adapted melanomas
is largely unknown. To this end, a third of melanomas display heightened expression of the transcriptional
coactivator PGC1α that integrates mitochondrial biogenesis and bioenergetic activity to ensure cellular
survival. Previously we found an inverse functional relationship between PGC1α expression and vertical
growth phase within primary melanoma that associates with poor patient prognosis, and genetic targeting of
PGC1α provoked enhanced metastatic traits in cell line models. Consistent with a functional role for adaptive
expression of PGC1α and enhanced malignancy traits, our current preliminary data supports that chronic
adaptation to BRAF-targeted drugs silences PGC1α expression through altered histone marks across its
promoter region. We now propose to seek the molecular mechanisms that attenuate PGC1α expression that
links enhanced metastatic spread and chronic adaptation to BRAF-targeted drugs. In an integrated study plan
that includes clinical melanoma specimens, established cell lines and in vivo tumor modeling, the experimental
design is focused on two aims: 1) to determine epigenetic mechanisms that silence PGC1α expression during
chronic adaptation to targeted BRAF(V600E) treatment; and 2) to identify collateral metabolic and epigenetic
vulnerabilities arising from chronic adaptation to targeted BRAF(V600E) treatment. Outcomes from these
studies will identify metabolites and epigenetic regulators that provoke vulnerabilities within alternate PGC1α-
dependent epigenetic states. Successful completion of the proposed study plan may help predict patients at
heightened clinical risk as well as provide means to break chronic adaptation to BRAF-targeted drugs.

## Key facts

- **NIH application ID:** 10369725
- **Project number:** 5R01CA181217-08
- **Recipient organization:** DANA-FARBER CANCER INST
- **Principal Investigator:** Pere Puigserver
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $307,356
- **Award type:** 5
- **Project period:** 2014-07-01 → 2025-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10369725

## Citation

> US National Institutes of Health, RePORTER application 10369725, Metabolic and epigenetic dependencies in melanomas during metastasis and targeted-drug resistance (5R01CA181217-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10369725. Licensed CC0.

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