# Identification of Druggable Targets to Complement Melanoma Therapy

> **NIH NIH R01** · UNIV OF ARKANSAS FOR MED SCIS · 2020 · $347,768

## Abstract

Abstract
 Historically, treatment options for melanoma were limited, and 5-year survival rates were <10% for
patients with advanced-stage disease. Recently, immune checkpoint inhibitors (ICIs) have shown encouraging
success for treatment of melanoma. However, approximately 40% of patients with advanced melanoma have
primary ICI resistance and sub-populations of initially responding patients develop secondary resistance. Can
we identify druggable molecular pathways in these non-responders to increase their ICI responsiveness and
potentially save lives? We have performed the only reported proteomics investigation of pre-ICI treatment
melanoma biopsies from responders and non-responders (6). In this preliminary study, we were able to
identify a panel of protein and histone epigenetic signatures that provided evidence for dysregulated
molecular pathways correlated to ICI responsiveness – providing the scientific premise for the outlined
studies. This preliminary study will be expanded to include 1) a larger number of patients, 2) patients with
primary and secondary ICI therapy resistance, and 3) tumor cell-type analyses. The overall goal of this
proposal is to combine state-of-the-art proteomics of patient tissues with pre-clinical animal models of ICI
responsiveness to create a functional proteomics pipeline for uncovering cellular protein and histone epigenetic
pathways functionally dysregulated in melanoma ICI non-responders. We will use a rigorous strategy to target
gene transcription and histone modifying proteins as these are upstream pathway effectors that can be
druggable. We hypothesize that certain proteins involved in gene transcription and posttranslational modification
of histones will be dysregulated in ICI non-responders and functionally coupled to molecular mechanisms of ICI
responsiveness, which will identify these proteins as high-priority, druggable candidates for complementing
existing ICI therapy. The aims of this study are: 1) perform functional proteomics to identify dysregulated gene
transcription protein pathways in melanoma ICI non-responders, 2) use high-resolution mass spectrometry to
identify dysregulated histone modifying protein pathways in melanoma ICI non-responders, and 3) determine
the functional significance in antitumor responses to ICI therapy for gene transcription and histone modifying
proteins dysregulated in melanoma ICI non-responders.

## Key facts

- **NIH application ID:** 9948599
- **Project number:** 5R01CA236209-02
- **Recipient organization:** UNIV OF ARKANSAS FOR MED SCIS
- **Principal Investigator:** Alan Tackett
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $347,768
- **Award type:** 5
- **Project period:** 2019-06-15 → 2024-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9948599

## Citation

> US National Institutes of Health, RePORTER application 9948599, Identification of Druggable Targets to Complement Melanoma Therapy (5R01CA236209-02). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9948599. Licensed CC0.

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