# Investigating concurrent Ras-pathway inhibition to optimize response to anti-PD-1 therapy in NRAS-mutant melanoma

> **NIH NIH F32** · VANDERBILT UNIVERSITY MEDICAL CENTER · 2020 · $71,430

## Abstract

Project Summary/Abstract
Melanoma is the most deadly form of skin cancer in the United States, with approximately 100,000 new
cases diagnosed annually. Patients diagnosed with metastatic melanoma have previously suffered an
abysmal 5-year survival rate, but a novel class of therapeutics termed immune checkpoint inhibitors
(ICI) have changed the landscape of melanoma treatment. ICI therapy is effective in up to 50% of
metastatic melanoma patients regardless of driver mutation, but work is needed to improve outcomes
for patients. One such strategy is to combine targeted therapies, such as those used in BRAF-mutant
melanoma, with ICI therapy. However, this strategy is limited by significant toxicity in BRAF-mutant
patients and is ineffective in the 20% of patients whose tumors harbor NRAS driver mutations.
Preliminary results suggest that rigosertib, a novel Ras-pathway inhibitor currently in clinical trials in
hematologic malignancy, may enhance anti-tumor immunity. Our preliminary data show that treatment
of melanoma tumors in mice with rigosertib induces an inflammatory tumor microenvironment, with
enriched total and CD8+ dendritic cells and CD45-MHCII+ cells, elevated levels of both CD4+ and CD8+
T cells, B cells and NK cells, but decreased levels of PD-1+ CD4+ T cells and tumor-infiltrating
macrophages. Rigosertib-treated melanoma tumors exhibit increased frequency and density of CD4+
and CD8+ T cells but very low levels of T cell activation in the tumor microenvironment. However, CD8+
T cells are strongly activated in the tumor-draining lymph nodes of rigosertib-treated tumors compared
to activation under vehicle treatment, suggesting a potent immunosuppressive effect mediated by tumor
microenvironment. These preliminary data provide a strong therapeutic basis for the use of immune
checkpoint inhibitors (e.g., anti-PD-1) in combination with rigosertib to enhance anti-tumor immunity
and optimize the treatment of melanoma. This hypothesis will be addressed by: 1) developing a
microbioreactor system for the co-culture of human NRAS-mutant melanoma organoids with patient-
matched leukocytes to evaluate the treatment response of NRAS-mutant melanoma cells to the
combination of rigosertib plus α-PD-1 therapy as compared to α-PD1 alone, and 2) generating
humanized patient-derived xenograft mouse models to determine the treatment response of NRAS-
mutant melanoma cells to the combination of rigosertib plus α-PD-1 therapy as compared to either
therapy alone. These studies will evaluate a promising novel treatment strategy with highly translational
relevance to melanoma patients while also establishing critical models for further preclinical studies of
immunotherapy.

## Key facts

- **NIH application ID:** 10067248
- **Project number:** 1F32CA254070-01
- **Recipient organization:** VANDERBILT UNIVERSITY MEDICAL CENTER
- **Principal Investigator:** Caroline Nebhan
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $71,430
- **Award type:** 1
- **Project period:** 2020-09-30 → 2022-09-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10067248

## Citation

> US National Institutes of Health, RePORTER application 10067248, Investigating concurrent Ras-pathway inhibition to optimize response to anti-PD-1 therapy in NRAS-mutant melanoma (1F32CA254070-01). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10067248. Licensed CC0.

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