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Identifying Therapeutic Targets for Stage III Melanoma

Award Number: R01CA244571
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/04/2019
PERIOD OF PERFORMANCE END DATE: 11/30/2024

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Identifying Therapeutic Targets for Stage III Melanoma - During the process of tumor progression, melanoma cells must exit the epidermis to form a dermal tumor, recruit lymphatic vessels, and then migrate to lymph nodes before metastasizing to distant organs. Melanoma prognosis directly correlates with tumor depth and lymph node metastasis. Therefore, ideal therapeutic agents for early stage melanoma would not only block melanoma invasion but also prevent tumor cells from accessing lymphatic vessels. Published work from our group determined that RhoJ, a gene that allows melanoma cells to resist BRAF oncogene-induced stress, is highly expressed in melanoma tumors that metastasize to the lymph node. RhoJ deletion stalled the growth of BRAF mutant melanoma tumors and inhibited the formation of BRAF mutant nevi in vivo. In addition to its selective role in controlling the growth of BRAF mutant melanocytes, RhoJ plays a specific role in tumor angiogenesis. RhoJ signaling in peritumoral endothelial cells induces them to generate vessels that serve as conduits for both nutrients to enter tumors and metastasizing cells to exit tumors. Recent yet unpublished work suggested that RhoJ deletion inhibited the ability of lymphatic endothelial cells to form vessels around tumors. Moreover, small molecules that inhibit RhoJ signaling seemed to not only block the growth of melanoma tumors in vivo, but also blocked the ability of endothelial cells to generate vessels to feed tumor cells in vitro. Here we propose that RhoJ has a dual role in tumor biology- it acts within the melanocyte to promote the formation of tumors and within the endothelial cells to promote the formation of lymphatic vessels around tumors in the skin, and blood vessels around tumors in distant organs. We use a combination of state of the art single cell genomics, in vivo imaging, novel pharmacologic agents, and transgenic mouse models to: 1) determine how RhoJ acts in the melanocyte to promote the growth of early stage tumors; 2) establish whether RhoJ acts in lymphatic endothelial cells to control tumor lymphangiogenesis; 3) assess the relative contributions of RhoJ to tumor growth and lymphanigogenesis/angiogenesis in vivo and in 3D models of human tumors. Completion of these studies will define a new therapeutic strategy that halts cancer progression by simultaneously targeting both tumor cells and the vessels that feed them.


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 = $397,059 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	5	12/14/2023	NON-COMPETING CONTINUATION	$376,161
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	5	4/17/2024	NON-COMPETING CONTINUATION	$20,898
														Subtotal = $397,059

Issue Date FY: 2023 ( Subtotal = $524,991 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	001	4	3/22/2023	NON-COMPETING CONTINUATION	$42,856
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Cancer Biology Research	000	4	11/23/2022	NON-COMPETING CONTINUATION	$482,135
														Subtotal = $524,991

Issue Date FY: 2022 ( Subtotal = $571,965 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	002	3	6/22/2022	NON-COMPETING CONTINUATION	$55,860
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	000	3	11/4/2021	NON-COMPETING CONTINUATION	$525,273
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	001	3	6/2/2022	NON-COMPETING CONTINUATION	-$9,168
														Subtotal = $571,965

Issue Date FY: 2021 ( Subtotal = $465,890 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	002	2	9/17/2021	NON-COMPETING CONTINUATION	$39,252
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	000	2	11/6/2020	NON-COMPETING CONTINUATION	$405,306
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	001	2	1/22/2021	NON-COMPETING CONTINUATION	$21,332
														Subtotal = $465,890

Issue Date FY: 2020 ( Subtotal = $425,106 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	001	1	1/23/2020	NEW	$10,439
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Cancer Biology Research	000	1	12/3/2019	NEW	$414,667
														Subtotal = $425,106

Grand Total All Awards = $2,385,011

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Identifying Therapeutic Targets for Stage III Melanoma

Award Number: R01CA244571

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/04/2019

PERIOD OF PERFORMANCE END DATE: 11/30/2024

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