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Enhancing sensitivity to GNAQ/11 pathway inhibitors by antagonizing the serotonin HTR2B receptor in uveal melanoma

Award Number: R21CA317293
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/27/2026
PERIOD OF PERFORMANCE END DATE: 07/31/2028

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Enhancing sensitivity to GNAQ/11 pathway inhibitors by antagonizing the serotonin HTR2B receptor in uveal melanoma - In uveal melanoma, more than 90% of patients have an activating mutation in the closely related heterotrimeric G protein a subunits (Ga) Gaq and Ga11 that are encoded by the GNAQ and GNA11 genes, respectively. These mutations in Gaq/11 occur predominantly at the codon for glutamine 209, resulting in either Q209L or Q209P mutations. Although the primary eye tumor is often successfully treated, ~50% of patients will develop metastatic disease. Targeted therapies and immunotherapies that have been successful in metastatic skin melanoma have been relatively ineffective in treating metastatic UM. Thus, there is an urgent need for the identification of novel therapeutic targets. Although these Gaq/11Q209L/P mutants have been thought to function independently of the canonical requirement for G protein-coupled receptor (GPCR) activation, and are thus often termed constitutively active, this exploratory project proposes a paradigm shift through the hypothesis that select GPCRs play a necessary role in maintaining the over-active state of mutant Gaq/11Q209L/P, and therefore GPCRs represent novel therapeutic targets. To test this idea, this project will focus on the serotonin 5-hydroxytryptamine (5-HT; serotonin) 2B receptor (HTR2B) GPCR, a receptor highly expressed and identified as a DepMap vulnerability in uveal melanoma cells. We propose that antagonizing HTR2B will shift endogenous Gaq/11Q209L/P in uveal melanoma cells into an inactive state and thus allow Gaq/11Q209L/P to be more efficiently inhibited by the natural product depsipeptide YM-254890, a selective inhibitor of Gaq/11. YM254890 is an effective inhibitor of uveal melanoma cell proliferation and tumor growth; however, enthusiasm for continued studies of the potential of YM-254890, and efforts to develop small molecule drugs based on YM-254890, has waned due to YM-254890 toxicity. This project will examine the ability of HTR2B antagonists to increase the potency, and thereby lessen toxicity, of YM-254890 in uveal melanoma cell lines and mouse models of metastatic uveal melanoma. Additionally, this project will investigate if HTR2B antagonism can render uveal melanoma cells to be more efficiently inhibited by clinically-relevant drugs, such as the protein kinase C inhibitor darovasertib, targeting activated signaling pathway components downstream of mutant Gaq/11Q209L/P. The use of murine models is necessary for this project because our proposal that HTR2B antagonists can lower the toxicity of YM-254890 or darovasertib requires a vertebrate animal model with the constituent multiple organ systems and complex interactions. Reductions in drug or inhibitor toxicity cannot be accurately studied using computational or cell culture models.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $403,686 )
2026	2026	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Treatment Research	000	1	7/27/2026	NEW	$403,686
														Subtotal = $403,686

Grand Total All Awards = $403,686

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Enhancing sensitivity to GNAQ/11 pathway inhibitors by antagonizing the serotonin HTR2B receptor in uveal melanoma

Award Number: R21CA317293

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/27/2026

PERIOD OF PERFORMANCE END DATE: 07/31/2028

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