# Targetable epigenetic and transcriptional mechanisms in melanoma that shape the microenvironment

> **NIH NIH P01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $1,463,720

## Abstract

Overall Summary
The overall goal of this proposal for renewal of P01 CA163222 is to further improve responses of metastatic
melanoma to MAP kinase pathway-targeted and immune checkpoint therapies, by targeting aberrant tumor-
intrinsic epigenetic regulation of gene expression, with a focus on enhancing the tumor immune
microenvironment. While those revolutionary therapies have provided major improvements in melanoma
outcomes, and advances in the past five years by us (in this Program Project) and others have substantially
improved the outlook for overcoming therapeutic resistance, the majority of patients still experience eventual
disease progression and fatality. Even with our significant successes in identifying resistance mechanisms and
novel potential therapeutic strategies, there remains an urgent need to discover additional mechanisms and
potential targets in acquired and intrinsic resistance to targeted and immune therapies for melanoma. Our
current approach incorporates mechanistic insights uncovered by investigators under this Program Project
Grant (PPG) and by other groups, namely the importance of genetic aberrations in epigenetic regulatory
machinery in resistance to therapy, at least partially by reshaping the tumor immune microenvironment, and as
potential targets for overcoming resistance. The three research projects in this proposal describe partially
uncovered mechanisms by which different epigenetic and transcriptional regulators drive melanoma resistance
to therapy and might be targeted therapeutically. These regulators include genomic copy number gains and
newly described gain-of-function mutations in the histone methyltransferase G9a, relocalization in chromatin of
the ETS transcription factor family member ETV1, and loss-of-function mutations in PBAF components of the
SWI/SNF chromatin remodeling complexes. These regulators will be investigated in vitro and in multiple
preclinical models in order to gain deeper understandings of their resistance mechanisms, particularly their
effects on the anti-tumor immune response, as well as to identify biomarkers of response to and assess the
feasibility of therapeutic strategies targeting them. Identification of resistance mediators and biomarkers of
response will be corroborated in human pre- and on-treatment melanoma biopsies, which are readily available
through our robust, independently funded Melanoma Patient Biopsy Program developed, in part, with funding
from this P01. Complex integration and analysis of complementary epigenetic and transcriptional data (RNA-
seq, ATAC-seq, and ChIP-seq) generated in all three projects will be performed by a Shared Resources Core
using state-of-the-art computational analysis and validation models. The expected outcome of these studies is
a more complete understanding of the mechanisms through which epigenetic and transcriptional regulators
drive resistance to targeted and immune cancer therapies, setting the stage for development of clinical tria...

## Key facts

- **NIH application ID:** 9989053
- **Project number:** 5P01CA163222-07
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** DAVID E FISHER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $1,463,720
- **Award type:** 5
- **Project period:** 2013-03-12 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9989053

## Citation

> US National Institutes of Health, RePORTER application 9989053, Targetable epigenetic and transcriptional mechanisms in melanoma that shape the microenvironment (5P01CA163222-07). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9989053. Licensed CC0.

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