# Research Project 1 - Targeting the MAPK and PI3K pathways in melanoma PDX

> **NIH NIH U54** · WISTAR INSTITUTE · 2020 · $352,598

## Abstract

Project Summary – Project 1
Melanoma cells adapt well when transplanted to immune-deficient mice and the group has established >450
PDX, which allow us to identify in-depth those subgroups of tumors that are most suitable for selected drugs.
The PDX have been extensively characterized for their growth properties in vitro and in vivo including
metastasis formation, somatic mutations in 108 genes through targeted sequencing, and expression of 305
proteins related to signal transduction. The models are superbly suited to investigate two major pathways that
are consistently activated in melanoma and in most other cancers: MAPK and PI3K pathways. Our overall
working hypothesis is that we can predict therapy responses based on the genetic, genomic, and biologic
signatures of tumors. We expect that we can define, short of a complete personalized approach, subgroups of
melanomas that will respond to new therapies and new combinations of therapies in a predictable way. Using
drugs that are available through NCI-CTEP, we will define in the first aim those melanomas that are most
sensitive to inhibitors of MET in combination with MAPK inhibitors. We will also investigate multi-kinase
inhibitors as single agents and in combination with MAPK inhibitors. Our working hypothesis is that in
subgroups of melanomas, MET as well as other receptor tyrosine kinases (PDGFRß, VEGFR, c-KIT, FGFR1)
and non-receptor kinases (SRC) are important targets. We expect to develop biomarkers that will pinpoint
those melanomas that are most (or least) susceptible to kinase inhibition. In the second aim, we will define
melanomas that are most sensitive to combined inhibition of the MAPK and PI3K pathways. Our working
hypothesis is that a subgroup of BRAF-mutant melanomas exists, which is highly susceptible to the
combination of BRAF/MEK with PI3K inhibitors. Based on our preliminary studies we will use loss of PTEN as
one biomarker for selection but expect further refinements, especially for tumors resistant to BRAF and
BRAF/MEK inhibitors. Since IGFR-1 signals predominantly through the PI3K pathway and is in selected
melanomas a key player in acquired resistance, we will include the appropriate CTEP inhibitor(s). At the same
time, we will determine whether isoform specific PI3K inhibitors are more appropriate in combination with
MAPK inhibitors. We expect to define biomarkers for the selection of both treatment-naïve and BRAF/MEK
inhibitor-resistant tumors. Our studies should provide a strong rationale for initiating clinical trials.

## Key facts

- **NIH application ID:** 10013151
- **Project number:** 5U54CA224070-03
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Meenhard F Herlyn
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $352,598
- **Award type:** 5
- **Project period:** 2017-09-30 → —

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10013151

## Citation

> US National Institutes of Health, RePORTER application 10013151, Research Project 1 - Targeting the MAPK and PI3K pathways in melanoma PDX (5U54CA224070-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10013151. Licensed CC0.

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