# Research Project 2 - Targeting Melanoma Tumor Survival and Apoptotic Machinery

> **NIH NIH U54** · WISTAR INSTITUTE · 2022 · $129,712

## Abstract

Project Summary – Project 2
Melanoma, the most aggressive form of skin cancer, is characterized by a very high rate of somatic mutations.
Approximately 50% of cutaneous melanomas have a mutation that affects the V600 residue in Braf. The
activity of the mutant form of the protein (BRAFV600) is markedly increased and results in constitutive activation
of the RAS-RAF-MAPK signaling pathway. This information has rapidly translated into clinical benefit, as five
targeted therapy regimens have been approved for the treatment of metastatic melanoma patients with a
BrafV600 mutation. While these agents have very high clinical response rates, unfortunately the majority of
patients develop resistance within 2 years. Further, these targeted therapies cannot be used in patients who
do not have a BrafV600 mutation. Thus, there remain unmet clinical needs to identify strategies to prevent
resistance to approved targeted therapies in metastatic melanoma patients with an activating BrafV600 mutation,
and new targeted therapy approaches for patients without a BrafV600 mutation (BRAF Wild-Type). While many
studies are ongoing to evaluate the therapeutic potential of other kinase inhibitors, there is growing evidence to
support the rationale for the testing of agents that target the apoptotic machinery. In contrast to many other
cancers, cutaneous melanomas have a low rate (~20%) of mutations in Tp53. Additional studies have shown
anti-apoptotic members of the BCL2 family of proteins can promote resistance to targeted therapies against
the RAS-RAF-MAPK pathway, and that pro-apoptotic proteins (i.e., BIM) are critical to their effectiveness.
Based on promising results in a limited number of preclinical models, clinical trials targeting the apoptotic
machinery in combination with RAS-RAF-MAPK pathway inhibitors are ongoing in metastatic melanoma
patients. However, currently there are no biomarkers to optimize patient selection for these strategies, nor
understanding of resistance mechanisms to them. The central hypothesis of this proposal is that specific
molecular features will predict sensitivity and resistance to combinatorial strategies utilizing pro-
apoptotic agents and MAPK pathway targeted therapies. In order to test this hypothesis we will evaluate
pro-apoptotic agents in combination with MAPK pathway inhibitors in molecularly characterized melanoma
PDX models, which accurately replicate the molecular features and heterogeneity of this disease. In AIM 1 we
will evaluate the efficacy and molecular effects of navitoclax, a BH3 mimetic that inhibits BCL2, alone and in
combination with dabrafenib (BRAFi) and trametinib (MEKi) in melanoma PDX with a BrafV600 mutation. These
experiments mirror an ongoing randomized phase II of these agents in metastatic melanoma patients, and the
results of that trial will be used to clinically validate markers associated with resistance in the PDX. In AIM 2
we will evaluate the efficacy of the MDM2 inhibitor AMG232, alone and in...

## Key facts

- **NIH application ID:** 10681845
- **Project number:** 3U54CA224070-04S3
- **Recipient organization:** WISTAR INSTITUTE
- **Principal Investigator:** Michael Davies
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $129,712
- **Award type:** 3
- **Project period:** 2017-09-30 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10681845

## Citation

> US National Institutes of Health, RePORTER application 10681845, Research Project 2 - Targeting Melanoma Tumor Survival and Apoptotic Machinery (3U54CA224070-04S3). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10681845. Licensed CC0.

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