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G alpha-q/11 Signaling and Inhibition in Ocular Melanoma

Award Number: R01CA234533
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/01/2018
PERIOD OF PERFORMANCE END DATE: 11/30/2023

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G alpha-q/11 Signaling and Inhibition in Ocular Melanoma - Project Summary Uveal melanoma (UM) is the most common intraocular tumor in adults. Nearly half of UM patients develop metastatic disease and survive one year or less. No effective therapy exists. Current interventions impair or destroy vision, yet do not improve morbidity or mortality caused by metastatic disease. Clinical trials of cytotoxic chemotherapeutics and immune checkpoint inhibitors have shown little efficacy. Mutant constitutively active forms of Gαq/11 that drive oncogenesis in ~90% of UM patients thus far have been undruggable. Inhibitors of signaling molecules downstream of these oncoproteins have failed to demonstrate significant clinical benefit. Effective therapy may require breakthroughs that enable direct targeting of constitutively active Gαq/11 or necessary but as yet unidentified downstream signaling cascades. This project fills these gaps by showing for the first time that constitutively active Gαq/11 can be trapped pharmacologically in the inactive GDP-bound state, thereby attenuating downstream signaling. The inhibitor causes Gαq/11-driven UM cells to arrest growth, die, or re-differentiate into melanocytic cells, whereas it has no effect on BRAF-driven UM cells. Inhibitor-treated UM cells has revealed a novel oncogenesis mechanism in which signaling by constitutively active Gαq/11 antagonizes epigenetic silencing mediated by polycomb repressive complex 2 (PRC2) to drive de-differentiation. Based on these breakthroughs, the following Aims will be pursued: 1) Identify novel druggable targets that mediate signaling between constitutively active Gαq/11 and PRC2 in UM cells; 2) Determine whether the Gαq/11 inhibitor provides vision-sparing therapeutic benefit in mouse models of primary and metastatic UM; and 3) Set the stage for clinical trials by determining which clinical subclasses of human primary UM tumors respond ex vivo to the Gαq/11 inhibitor. In summary, this project provides unprecedented opportunity to determine whether direct pharmacological inhibition of mutant constitutively active Gαq/11 could provide the first effective and potentially vision-sparing therapeutic option for treating 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: 2024 ( Subtotal = $0 )
2024	2022	WASHINGTON UNIVERSITY, THE	1 BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	4	4/11/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $567,921 )
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	4	5/19/2022	NON-COMPETING CONTINUATION	$46,360
2022	2022	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	4	11/9/2021	NON-COMPETING CONTINUATION	$521,561
														Subtotal = $567,921

Issue Date FY: 2021 ( Subtotal = $579,510 )
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	3	1/22/2021	NON-COMPETING CONTINUATION	$28,975
2021	2021	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	3	11/20/2020	NON-COMPETING CONTINUATION	$550,535
														Subtotal = $579,510

Issue Date FY: 2020 ( Subtotal = $578,437 )
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	2	11/4/2019	NON-COMPETING CONTINUATION	$520,593
2020	2020	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	001	2	1/13/2020	NON-COMPETING CONTINUATION	$57,844
														Subtotal = $578,437

Issue Date FY: 2019 ( Subtotal = $574,451 )
2019	2019	WASHINGTON UNIVERSITY, THE	ONE BROOKINGS DR	SAINT LOUIS	MO	63130	SAINT LOUIS	USA	Cancer Treatment Research	000	1	11/28/2018	NEW	$574,451
														Subtotal = $574,451

Grand Total All Awards = $2,300,319

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G alpha-q/11 Signaling and Inhibition in Ocular Melanoma

Award Number: R01CA234533

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/01/2018

PERIOD OF PERFORMANCE END DATE: 11/30/2023

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