# Therapeutic Targeting of Gaq in Uveal Melanoma

> **NIH NIH F31** · SLOAN-KETTERING INST CAN RESEARCH · 2020 · $40,295

## Abstract

PROJECT SUMMARY
Uveal melanoma (UVM) is the most common intraocular malignancy, which represents about 5% of all
melanoma cases per year in the United States. Half of all patients eventually develop metastatic disease,
resulting in an average survival rate of six months and a five year survival rate of ~15%. Recent studies have
revealed the underlying genetic landscape of uveal melanoma but have not resulted in any therapeutic options
to effectively treat UVM. UVMs harbor mutually exclusive activating mutations in GPCR signaling: ~90% in G-
protein alpha q (Gq) subunits GNAQ/GNA11, ~5% in the GPCR CYSLTR2, and ~4% in a downstream effector
PLCB4. These mutations aberrantly activate canonical PLCβ signaling: cleavage of PIP2 into DAG and IP3 both
of which lead to PKC activation. In addition to uveal melanoma, recent studies have shown this exact pathway
to be activated in a subset of cutaneous and mucosal melanomas as well as other diseases like blue nevi,
leptomeningeal melanocytic neoplasms (LMNs), and Sturge-Weber syndrome. My project focuses on
understanding how Gq signals in UVM tumorigenesis and if Gq inhibition has therapeutic potential in UVM by
addressing the following aims: 1) Using a highly specific Gq inhibitor, I will ask how Gq inhibition effects
different activating mutations in UVM using representative in vitro models. I have generated melanocytes
dependent on different mutations in the PLCβ pathway to study pathway inhibition and therapeutic efficacy.
Based on my preliminary data I will also interrogate the mechanistic basis for Gq inhibition sensitivity in GNAQ
mutant driven melanocytes. 2) Determine clinical potential of this drug by testing its pharmacological properties
in vivo. Using the melanocytes I have generated along with UVM cell lines and our GEMM we will be able to
throughouly test the drugs efficacy in mice and ability to inhibit tumor growth in a variety of xenograft
experiments. 3) Taking advantage of the ability to inhibit active Gq, I will aim to identify other pathways
activated downstream of Gq using proteomic and transcriptomic approaches. This may provide alternative
therapeutic strategies to target this recalcitrant disease. The outcome of this research will indicate the
effectiveness of Gq inhibition in UVM as well as elucidate currently unknown signaling pathways essential for
UVM tumorigenesis. The Chen and Chi labs provide a diverse set of resources and experiences that will
greatly benefit my development into an independent researcher. The GSK program provides a solid foundation
for scientific achievement with a core course covering vast topics with leaders in the field, graduate seminar
series, topical journal clubs, and access to Tri-institutional resources. MSKCC exemplifies a translational
science environment by bringing together physicians and scientists who collaborate on cutting edge research
to advance treatments for cancer patients.

## Key facts

- **NIH application ID:** 9960301
- **Project number:** 5F31CA236030-02
- **Recipient organization:** SLOAN-KETTERING INST CAN RESEARCH
- **Principal Investigator:** Tyler Hitchman
- **Activity code:** F31 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $40,295
- **Award type:** 5
- **Project period:** 2019-06-17 → 2021-04-21

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9960301

## Citation

> US National Institutes of Health, RePORTER application 9960301, Therapeutic Targeting of Gaq in Uveal Melanoma (5F31CA236030-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9960301. Licensed CC0.

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