# Mechanisms of non-genetic variation in melanoma

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $195,134

## Abstract

Project Summary/Abstract
This proposal details a five year training plan for the development of a research program focused on
non-genetic mechanisms of therapy resistance in melanoma. Therapies that target the MAPK pathway
in melanoma have remarkable success in shrinking patients’ initial tumors but disease recurs, often
without new mutations that explain therapy failure. This appears to be due to a small population of rare
cells present in the initial tumor that display high levels of resistance genes such as epidermal growth
factor receptor (EGFR) and are not killed by initial MAPK targeted therapy. The mechanisms that drive
formation of these rare pre-resistant cells are unknown, though preliminary studies implicate gene
regulation by enhancers. The goals of this research proposal are to characterize the key genetic
pathways that define pre-resistant cells in patient tumors, identify enhancers that drive expression of
resistance genes and cellular variation, and to identify pharmacologic targets for preventing therapy
resistance. Since EGFR plays an important role in many cancers and non-genetic variation appears to
undergird treatment failure in many different malignancies, the implications of this work for human
disease may be far-reaching. The work will be mentored by Phillip A. Sharp at the Massachusetts
Institute of Technology, a leader in understanding gene regulation in cancer and whose laboratory has
produced numerous distinguished alumni.
I am a practicing molecular pathologist at the Massachusetts General Hospital interested in how
variation arises naturally within biological systems. In diagnostic pathology, we are attempting to
achieve ever greater ‘personalized medicine’ in cancer treatment using sequencing. To achieve the
best precision medicine possible, we must understand the mechanisms by which tumors evade therapy
that go beyond genetic changes such as mutations. This will allow us to build better, more accurate
diagnostics and give our oncologist colleagues the best actionable information. My career objective
during the proposal period is to obtain a tenure-track position at an academic medical center continuing
work as a Principal Investigator. Specifically, during the proposal period I will gain experience with
melanoma model systems, enhancer biology, genomics, and systems biology approaches. My long
term objective is to define how variation and heterogeneity arise within biological systems and how we
can diagnose and manipulate these processes in human disease.

## Key facts

- **NIH application ID:** 10055322
- **Project number:** 1K08CA237856-01A1
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Salil Garg
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $195,134
- **Award type:** 1
- **Project period:** 2020-09-01 → 2025-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10055322

## Citation

> US National Institutes of Health, RePORTER application 10055322, Mechanisms of non-genetic variation in melanoma (1K08CA237856-01A1). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10055322. Licensed CC0.

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