Thursday, December 18, 2025 12/18/2025

RasGRP3 and Protein Kinase D as therapeutic targets for Uveal Melanoma

Award Number: R01CA269338
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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RasGRP3 and Protein Kinase D as therapeutic targets for Uveal Melanoma - Project summary: Uveal melanoma (UM) accounts for approximately 5% of all melanomas and is the most lethal type of melanoma. 50% of UM patients develop metastasis, mostly to the liver, an invariably lethal complication, which currently cannot be effectively treated. Despite dramatic successes in other melanoma subtypes, immune checkpoint blockade, and targeted therapies have been largely ineffective in metastatic UM and there is an urgent need to identify effective therapies. UM lacks mutations in BRAF, NRAS, NF1 and KIT common in cutaneous melanomas and is genetically defined by mutations in the Gaq signaling pathway. We discovered that RasGRP3, a Ras-guanyl nucleotide exchange factor (RasGEF), is dramatically overexpressed in UM compared to other melanoma subtypes and cancers and links the constitutively activated Gaq pathway to the MAP- kinase pathway. RasGRP3 is also directly activated by oncogenic Gaq signaling via mechanisms that partially depend on PKC. We hypothesize that RasGRP3 is a therapeutic target in UM and seek to understand the mechanism behind its marked upregulation to identify alternative targets for therapy. Our preliminary data implicate protein kinase D (PKD) downstream of PKC to be directly involved in RasGRP3 regulation. Our data also demonstrate that PKD is involved in the adaptive resistance that undermines the efficacy of MEK inhibitors. As a druggable kinase, PKD thus is a possible therapeutic target in UM. In this proposal, we will evaluate both RasGRP3 and PKD as therapeutic targets using newly developed genetically engineered and xenograft models of UM metastatic to the liver and investigate the underlying mechanism of RasGRP3 upregulation in UM (Aim 1 and 2). In Aim 3, we will dissect the mechanism underlying the adaptive resistance to MEK inhibition, which represents a key bottleneck limiting the therapeutic efficacy of MEK inhibition, to identify rational therapy combinations that overcome this resistance and improve the therapeutic efficacy of MEK inhibition in the setting of metastatic UM.


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 = $409,450 )
2026	2026	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	000	4	12/15/2025	NON-COMPETING CONTINUATION	$409,450
														Subtotal = $409,450

Issue Date FY: 2025 ( Subtotal = $454,865 )
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	001	3	5/30/2025	NON-COMPETING CONTINUATION	$45,487
2025	2025	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	000	3	12/27/2024	NON-COMPETING CONTINUATION	$409,378
														Subtotal = $454,865

Issue Date FY: 2024 ( Subtotal = $432,122 )
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94103	SAN FRANCISCO	USA	Cancer Treatment Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$22,744
2024	2024	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	2	1/9/2024	NON-COMPETING CONTINUATION	$409,378
														Subtotal = $432,122

Issue Date FY: 2023 ( Subtotal = $454,716 )
2023	2023	REGENTS OF THE UNIVERSITY OF CALIFORNIA, SAN FRANCISCO, THE	1855 FOLSOM ST STE 425	SAN FRANCISCO	CA	94143	SAN FRANCISCO	USA	Cancer Treatment Research	000	1	11/28/2022	NEW	$454,716
														Subtotal = $454,716

Grand Total All Awards = $1,751,153

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RasGRP3 and Protein Kinase D as therapeutic targets for Uveal Melanoma

Award Number: R01CA269338

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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