# A High-Throughput Model for Human Melanoma

> **NIH NIH R01** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $289,750

## Abstract

Significant advances in melanoma research have resulted in new therapies that have remarkably improved the
management and overall survival of melanoma. However, many patients still succumb to the disease and more
than half of all melanoma deaths are due to brain metastases. As a means to overcome this challenge, we
developed a novel mouse model that allows postnatal delivery of genes of interest to melanocytes. Using
genomic and proteomic data from human melanoma samples, we tested several gene combinations for their
ability to induce metastatic melanoma in vivo. Hyperactivation of the PI3K/AKT pathway in the context of mutant
BRAF and CDKN2A loss resulted in the development of spontaneous melanoma with full penetrance and a
mean survival of only 6 weeks. The majority of these mice also developed multiple metastases to the lungs and
brain. This model mimics the human disease genetically, histologically, and by sites of metastasis. Importantly,
this model system provides a powerful platform to further study the mechanisms of melanoma metastasis.
Elucidation of this network will allow the identification of key pathway nodes that represent potential therapeutic
targets to disrupt this process. We used next generation sequencing and proteomics analysis of non-metastatic
and metastatic tumor samples to identify downstream targets of AKT1 implicated in melanoma brain metastasis.
Our data showed that tumors expressing activated AKT1 displayed elevated levels of focal adhesion (FA) factors
and phosphorylated focal adhesion kinase (P-FAK). In addition, mutant AKT1 expression increased invasion and
this was reduced by pharmacological inhibition of either AKT or FAK. Moreover, loss of PTEN, which also results
in increased FAK activity, cooperated with activated AKT1 to further enhance brain metastasis in vivo. Despite
these promising preliminary findings, a critical gap still remains in understanding whether and how FAK promotes
melanoma brain metastasis, and whether the AKT1-FAK-PTEN axis can be exploited as a therapeutic target in
this disease. Our long-term goal is to use this knowledge to develop novel melanoma therapies and improve
patient outcomes. Pursuant to this goal, we have generated a diverse collection of state-of-the-art research tools
and assembled a talented team of scientists and clinicians with a track record of productive collaboration to carry
out and critically evaluate the results of the proposed aims. Using these unique resources, we propose to test
the following hypotheses: 1) AKT1→ FAK signaling is essential for the development of melanoma brain
metastases; 2) Combined inhibition of BRAFV600E, MEK, and FAK is superior to standard of care targeted therapy
and; 3) Loss of PTEN expression results in sustained FAK phosphorylation, which enhances the development
of melanoma brain metastases. Successful completion of the aims in this proposal will significantly impact the
field by laying the groundwork for translation into clinical trials...

## Key facts

- **NIH application ID:** 10120567
- **Project number:** 2R01CA121118-11A1
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Sheri L Holmen
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $289,750
- **Award type:** 2
- **Project period:** 2007-04-13 → 2025-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10120567

## Citation

> US National Institutes of Health, RePORTER application 10120567, A High-Throughput Model for Human Melanoma (2R01CA121118-11A1). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10120567. Licensed CC0.

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