# Development of a new molecular predictor for risk of distant metastases in melanoma

> **NIH NIH R21** · UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH · 2021 · $142,588

## Abstract

New therapies have significantly improved the management of melanoma but brain metastases continue to be
a major component of treatment failure. The ability to identify those patients who are at highest risk of developing
brain metastases is very challenging with current methods. Successful development of sensitive and specific
prognostic methods for prediction of brain metastases risk in earlier stage melanoma patients would enable the
development of more effective surveillance strategies and prospective trials for chemoprevention of brain
metastasis development in these high-risk patients. Gene expression signatures have been shown to be
prognostic in multiple cancer types and prior gene expression profiles (GEP) of metastases have been published
for melanoma. However, the sensitivity and specificity as well as the positive and negative predictive value of
these assays remains suboptimal and no specific molecular signature has been described for predicting risk of
brain metastases. We analyzed multiple independent gene expression datasets and identified a list of genes that
robustly predicts the development of brain metastases. To translate this finding to the clinic, we will optimize the
most robust genes in formalin-fixed paraffin embedded tissue and integrate the findings with other relevant
biomarkers of disease progression. Recent analysis of metastatic lesions from melanoma patients revealed that
brain metastases had significantly higher levels of active phosphorylated AKT (pAKT) than extracranial
metastases. We validated these findings by expressing activated AKT in our established melanoma mouse
model and observed lung and brain metastases in ~80% of the mice. Based on these data, we hypothesize that
the combination of an optimized gene expression signature along with other relevant clinical and pathologic
variables, will identify those melanoma patients at highest risk for the development of brain metastases. We will
use our rich resource of patient samples to test our hypothesis. While therapeutic intervention to prevent brain
metastases in melanoma is our long-term goal, in order for this to be implemented most effectively it is crucial
that we develop more accurate methods to identify those patients at highest risk for the development of
metastatic disease before those metastases occur. The objective of this study is to generate a clinical/molecular
predictor for risk of brain metastases in melanoma patients and to validate the sensitivity and specificity of an
optimized clinical/molecular prognostic assay for the development of brain metastases in a retrospective study
of Stage II/III melanoma patients. With the recent approval of adjuvant therapies that include stage III disease,
we have an enormous opportunity to intervene when there is minimal or non-detectable disease and not only
prevent melanoma recurrence but also improve overall survival. As these adjuvant therapies are not without risk,
successful completion of the aims in...

## Key facts

- **NIH application ID:** 10078265
- **Project number:** 5R21CA245577-02
- **Recipient organization:** UTAH STATE HIGHER EDUCATION SYSTEM--UNIVERSITY OF UTAH
- **Principal Investigator:** Sheri L Holmen
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $142,588
- **Award type:** 5
- **Project period:** 2020-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10078265

## Citation

> US National Institutes of Health, RePORTER application 10078265, Development of a new molecular predictor for risk of distant metastases in melanoma (5R21CA245577-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10078265. Licensed CC0.

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