# Defining the Role of Metabolic Heterogeneity in Melanoma Dissemination and Therapy Escape

> **NIH NIH R00** · H. LEE MOFFITT CANCER CTR & RES INST · 2022 · $249,000

## Abstract

PROJECT SUMMARY/ ABSTRACT
Despite promising initial responses, most BRAF-mutant melanoma patients eventually fail on BRAF inhibitor
therapy. The task of understanding therapeutic escape and dissemination is complicated further by the
countless number of resistance mechanisms identified so far and the realization that multiple cellular
phenotypes may exists within a single genotype. The roles of intra-tumoral heterogeneity in progression and
drug resistance are poorly understood, and we submit that strategies tackling this diversity are needed for
durable therapeutic responses in patients. We hypothesize that: (i) drug-induced tumor cell phenotypic
heterogeneity is driven by the development of inter-dependent and cooperative metabolic niches that promote
tumor dissemination and affect the response to therapeutics; and (ii) therapeutic approaches that exploit intra-
clonal metabolic competition will give more durable responses in melanoma patients. We will define the
metabolic landscape of OXPHOS-dependent and glycolysis-dependent subpopulations in cell culture,
xenografts, patient-derived xenografts (PDX) and patient specimens using single-cell RNAseq, global
metabolomics and targeted expression panels. We will test how OXPHOS-dependent and glycolysis-
dependent subpopulations cooperate to drive metastasis and define the drug sensitivities of the individual
subpopulations in vitro and in xenografts and PDXs. We will test if disrupting either OXPHOS or glycolysis,
pharmacologically or through gene expression targeting, shapes the metastatic potential or the emergence and
heterogeneity of drug resistant subpopulations. We will devise a mathematical model to define optimal,
evolutionary-informed dosing of BRAF/MEK plus metabolic inhibitor combinations that impair clonal
cooperation and maximize duration of the therapeutic response. These models will be validated in vitro and in
PDX models.
The K99/R00 award would allow the candidate to conduct the proposed studies under the continued guidance
of their primary mentor, Dr. John Cleveland, together with a panel of co-mentors who are renowned experts in
melanoma biology, PDX modeling, cancer evolution, metabolism, and statistical and computational
approaches to systems-wide large-scale data set analysis. During the K99 phase, the candidate will further
develop their knowledge in melanoma metabolism and evolutionary biology, as well as their technical abilities
in mass-spectrometry-based metabolomics, advanced computational biology, bioinformatics and biostatistics.
With the help of their committee and various seminars, courses and workshops, the candidate will become a
stronger scientist, manager, grant writer and mentor, all skills necessary to be an independent investigator.
Overall, the proposed work will provide the rationale for therapeutic approaches that exploit intra-clonal
metabolic competition to give more durable responses in melanoma patients, as well as a timely career
transition for a candi...

## Key facts

- **NIH application ID:** 10478200
- **Project number:** 5R00CA226679-05
- **Recipient organization:** H. LEE MOFFITT CANCER CTR & RES INST
- **Principal Investigator:** Inna Smalley
- **Activity code:** R00 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $249,000
- **Award type:** 5
- **Project period:** 2020-09-01 → 2024-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10478200

## Citation

> US National Institutes of Health, RePORTER application 10478200, Defining the Role of Metabolic Heterogeneity in Melanoma Dissemination and Therapy Escape (5R00CA226679-05). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10478200. Licensed CC0.

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