# Metastatic Clonal Heterogeneity and its Impact on Melanoma Therapeutic Resistance

> **NIH NIH R01** · UNIVERSITY OF CALIFORNIA LOS ANGELES · 2021 · $462,960

## Abstract

ABSTRACT
Melanomas metastasizing to different organs often display heterogenous responses to therapies such as BRAF
inhibitor or anti-PD-1 (aPD-1) immunotherapy. This heterogeneity of responses may be due to strictly tumor
cell-intrinsic biological differences or more likely co-adaptation of the tumors with organ site-specific
microenvironments. However, most patient-centric studies of metastatic melanoma biology and/or therapeutic
responses are limited to one tumor per patient, with a predominance of tumors from more accessible sites such
as the skin. Thus, there is a dearth of clinically relevant knowledge of organ site-specific adaptations of
melanoma metastases and their possible influence on therapeutic responses. This project will derive this
knowledge through comprehensive analysis on not only melanoma lesions at distinct organ sites but also their
adjacent and non-adjacent normal organ tissues from warm autopsies.
Through integrative genomic and transcriptomic analysis of triplets of tumor, adjacent normal and non-adjacent
normal specimens, this study sets out to dissect the co-evolution of the tumor and its host organs. The
preliminary analyses have already revealed several pathway activations that may be related to MAPK inhibitor
(MAPKi) or immune checkpoint blockade (ICB) resistance in the brain, liver and spleen metastases. Aiming for
a larger set of specimens, the researchers will assess the tumor heterogeneity (at the genomic, transcriptomic
and pathway activation levels), their association with metastatic growth and MAPKi/ICB response patterns in
each metastatic organ. In parallel, the research team will examine the tumor-adjacent normal tissues' cellular
composition and pathway activations. These will also be correlated with organ-specific tumor growth and
treatment resistance. The PI's experiences in large omic integration analyses of MAPKi and ICB resistant
tumors will be a tremendous asset for the success of the proposed work. This study is expected to discover and
validate heretofore unknown determinants of organ-specific metastasis in melanoma and novel mechanism(s)
of resistance to MAPKi and ICB.

## Key facts

- **NIH application ID:** 10130463
- **Project number:** 5R01CA236910-02
- **Recipient organization:** UNIVERSITY OF CALIFORNIA LOS ANGELES
- **Principal Investigator:** Willy Hugo
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $462,960
- **Award type:** 5
- **Project period:** 2020-05-01 → 2025-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10130463

## Citation

> US National Institutes of Health, RePORTER application 10130463, Metastatic Clonal Heterogeneity and its Impact on Melanoma Therapeutic Resistance (5R01CA236910-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10130463. Licensed CC0.

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