# Rational approaches to melanoma therapy (PDXNet Administrative Supplement to R01CA121118)

> **NIH NIH U54** · WISTAR INSTITUTE · 2021 · $120,000

## Abstract

Project Summary – CA224070
The outcomes of patients with metastatic melanoma have improved dramatically over the last decade due to an
improved understanding of the molecular drivers of this disease. In particular, multiple targeted therapy regimens
have been approved for patients with a BRAFV600E/K mutation, which are present in ~50% of cutaneous melanomas.
These treatments achieve clinical responses in ~80% of patients with a BRAFV600E/K mutation, thus providing proof-
of-concept of the therapeutic potential for personalized therapeutic strategies. However, most of the patients will
progress within 2 years of starting those therapies. Further, currently there are no targeted therapies that have been
shown to be effective in patients with a wild-type BRAF. Thus, there are unmet clinical needs to develop treatments
that prevent or overcome resistance to existing therapies for patients with a BRAFV600E/K mutation, and that are
effective in patients without a BRAF mutation. In order to facilitate the development of new therapeutic strategies,
over the last 5 years we have led a major effort to develop a broad collection of PDX models to reflect the clinical,
histological, and genetic heterogeneity of this disease. Our collection of >450 PDX models represents one of the
largest collections for any human malignancy, and our initial testing demonstrates that the collection accurately
recapituluates the oncogenic drivers and molecular heterogeneity that is observed in patients. This collection also
includes a subset of PDX established from patients with acquired resistance to targeted therapies that have been
maintained on those agents in vivo to sustain their resistant phenotype. Together these efforts have generated a
robust resource to develop, refine, and prioritize new personalized combinatorial therapies for patients. Thus, we
propose to establish a multi-disciplinary and multi-institutional PDTC Program focused on the use and continued
expansion of our robutst melanoma PDX collection to identify new therapeutic approaches that fill important clinical
gaps in this disease. Project 1 will characterize kinase inhibitors targeting receptor tyrosine kinases (RTKs) and the
PI3K-AKT pathway in combination with approved targeted therapies in PDX models in treatment-naïve and drug-
resistant BRAFV600E/K-mutant melanomas. Project 2 will characterize targeting the apoptotic machinery of cancer
cells as a combinatorial approach with MAPK pathway inhibitors in PDX with and without BRAFV600E/K mutations,
including in subsets with aberrancies in anti-apoptotic genes. Both Projects will utilize baseline characteristics of the
PDX models to identify potential biomarkers of sensitivity and resistance to guide personalized patient selection for
future clinical testing. In addition, tumors will be analyzed for treatment-induced effects that correlate with sensitivity
to identified resistance mechanisms and potential new combinatorial strategies. Finally, markers id...

## Key facts

- **NIH application ID:** 10371684
- **Project number:** 3U54CA224070-04S1
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Michael Davies
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $120,000
- **Award type:** 3
- **Project period:** 2017-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10371684

## Citation

> US National Institutes of Health, RePORTER application 10371684, Rational approaches to melanoma therapy (PDXNet Administrative Supplement to R01CA121118) (3U54CA224070-04S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10371684. Licensed CC0.

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