# Functional precision approaches to overcome intrinsic and acquired drug resistance in melanoma

> **NIH NIH U54** · WISTAR INSTITUTE · 2024 · $380,225

## Abstract

Project Summary – Project 1
 Although significant progress has been made treating melanoma, less than 30% of patients achieve long-term
responses and almost 70% of patients are resistant to any approved therapies including immunotherapies and targeted
therapies. Therefore, novel strategies to overcome intrinsic and acquired drug resistance are sorely needed.
This Patient Derived Xenograft (PDX) Development and Trial Center (T-PDTC) research project will capitalize
on our extensive collection of >500 clinically annotated and molecularly characterized PDXs to develop functional
precision therapies to offset melanoma drug resistance. Our working hypothesis is that the tumor’s genomic,
molecular and drug response profiles in organoids and PDXs can be leveraged to develop clinically
translatable precision therapies. We also posit that our pre-clinical pipeline will identify markers to select tumors that
are most likely to respond to a given treatment, offsetting drug resistance and achieving long-term responses, with no
overt toxicity. We expect that our pre-clinical studies will help prioritize the clinical testing of targeted agents for
the treatment of melanoma.
 Our melanoma PDX collection has been extensively characterized for growth properties, metastasis
formation, somatic mutations through targeted and whole exome sequencing, RNA expression and expression
of ~500 proteins related to signal transduction. Our models are superbly suited to investigate combination
therapies to overcome or prevent drug resistance as they represent the heterogeneity of melanoma. To do this,
two Specific Aims are proposed: Aim 1, will test the hypothesis that drug resistant melanomas harboring a
transcriptional signature termed ‘innate anti–PD-1 resistance signature’ (IPRES+), which is associated with resistance
to anti-PD1 and MAPK inhibitors, will respond to the combination of BET and MEK inhibitors. We will optimize this
treatment regimen and further define markers of response and resistance. For IPRESNeg tumors, we will integrate
genomic, transcriptional and proteomic analyses to pair tumors with drugs matching their molecular profile; this
will allow for establishing optimal combination and dosing strategies. In aim 2, we will conduct temporal and
spatial transcriptomic and proteomic analysis to identify and profile drug tolerant subpopulations. Our goal is to monitor
treatment response and intervene with combinations aimed at killing both the bulk of the tumor and rare drug
tolerant/persister subpopulations preventing the emergence of resistance. We anticipate that our studies will provide
critical information needed to translate effective and long-lasting precision therapies from the bench to bedside and
improve the outcomes of melanoma patients.

## Key facts

- **NIH application ID:** 10911351
- **Project number:** 5U54CA224070-06
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Jessie Villanueva
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $380,225
- **Award type:** 5
- **Project period:** 2017-09-01 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10911351

## Citation

> US National Institutes of Health, RePORTER application 10911351, Functional precision approaches to overcome intrinsic and acquired drug resistance in melanoma (5U54CA224070-06). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10911351. Licensed CC0.

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