# Project 2:  Targeting differentiation-linked redox sensitivity in melanoma

> **NIH NIH P01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $517,922

## Abstract

PROJECT 2 ABSTRACT
Melanoma treatment has had instrumental advances in two modern modalities: immunotherapy and targeted
kinase inhibitor treatments. Nevertheless, there is a crucial clinical need to address dedifferentiation as a
resistance mechanism to modern melanoma therapies. Notably, dedifferentiation is a documented cross-
resistance mechanism that impacts both of the new expanding standards of care: BRAF and MEK kinase inhibitor
therapies, and immunotherapies such as immune checkpoint blockade (e.g. anti-PD-1/PD-L1). Our discovery of
a new dedifferentiation-associated sensitivity to iron-dependent oxidative stress (ferroptosis), provides a new
angle from which to complement current standard of care therapies for melanoma. In our studies, sensitivity to
ferroptosis is an Achilles heel for dedifferentiated cells independent of whether they were dedifferentiated at
baseline, or induced to dedifferentiate by BRAF and MEK inhibitor therapy or by immunotherapy associated
cytokines. Thus, using preclinical models, we will further pursue this orthogonal sensitivity to prevent the
dedifferentiation escape route.
Our discovery and proposed experiments brings the programmed cell death process of ferroptosis into the field
of melanoma and melanocytes. We will investigate how the redox stress protection mechanisms specific to
redox-regulated melanin production in melanocytes interact with iron metabolism, ferritinophagy and ferroptosis
in melanoma cells. Studies in the melanoma and melanocyte context will help advance our knowledge of this
relatively recently discovered cell death mechanism. We will test the efficacy of combining ferroptosis induction
with either kinase inhibitor therapy, or checkpoint inhibitor immunotherapy using preclinical models. We will
interrogate human samples from clinical trials to assess the immunotherapy contexts in which dedifferentiation
presents the highest clinical challenge and opportunity. Our discovery of dedifferentiation-linked ferroptosis
sensitivity was the result of an integrative genomics and pharmacogenomics approach. We will continue to
expand our framework of the regulation of melanoma dedifferentiation using integrative genomics to delineate
transcription and epigenetic regulatory programs. To expand upon the multiple links between metabolism, redox
buffering, differentiation, and ferroptosis, we will incorporate metabolomics and lipidomics in our discovery and
mechanistic delineation approaches. Our goal in these aims is to mechanistically understand and enhance the
therapeutic approach of targeting the melanoma dedifferentiation resistance escape route.

## Key facts

- **NIH application ID:** 10261397
- **Project number:** 5P01CA244118-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** THOMAS G GRAEBER
- **Activity code:** P01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $517,922
- **Award type:** 5
- **Project period:** 2020-09-11 → 2025-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10261397

## Citation

> US National Institutes of Health, RePORTER application 10261397, Project 2:  Targeting differentiation-linked redox sensitivity in melanoma (5P01CA244118-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10261397. Licensed CC0.

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