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Combination Therapies to Defeat Melanoma Resistance

Award Number: P01CA244118
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/11/2020
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Combination Therapies to Defeat Melanoma Resistance - OVERALL ABSTRACT This is the A1 re-submission of a new Program Project Grant (PPG) focused on studying how advanced melanoma resists targeted therapies and immunotherapies, either upfront or after a period of response, and this information is aimed at defining the vulnerabilities that provide new therapeutic opportunities. Project 1 (Roger Lo) focuses on the study of resistance of NRASMUT melanomas to targeted therapies and immunotherapies. Studies will focus on discovering and co-targeting genomic, epigenomic and/or signaling alterations causative of MEK inhibitor (MEKi) resistance; exploiting MEKi-addiction of MEKi-resistant clones; and identifying immune targets to augment MEKi efficacy and suppress MEKi resistance in vivo in NRASMUT melanomas. Project 2 (Thomas Graeber) focuses on studying molecular mechanisms and targeting of the ferroptosis sensitivity of dedifferentiated melanomas in preclinical models. In addition, this project will also define and target master regulatory programs underlying melanoma dedifferentiation. Project 3 (Antoni Ribas) focuses on studying primary and acquired resistance to PD-1 blockade immunotherapy, especially defining mutations in the interferon gamma and antigen presentation pathways, as well as reversing T cell exclusion from cancers. The understanding of these resistance mechanisms will rationalize combinatorial therapies to be tested in preclinical mouse models. The three projects are supported by three cores, the Administrative and Statistics Core (Antoni Ribas), the Biospecimen Core (Begonya Comin-Anduix) and the Patient-Derived Xenograft (PDX)/Syngeneic Mouse Core (Gatien Moriceau). The proposed research addresses scientific problems that require integrated and collaborative teamwork. In Project 1, the study of MAPK inhibitor addiction, resulting in sensitivity to drugs that induce parthanatos (a caspase-independent mode of cell death), can be applied to the melanoma dedifferentiation states studied in Project 2 and will synergize with immunotherapies studied in Project 3. Similarly, in Project 2, the dedifferentiated melanoma phenotype, which is a resistance mechanism to MAPK inhibitors and also induced by T cell-released cytokines, leads to sensitivity to ferroptosis- (an iron-dependent form of nonapoptotic cell death) inducing agents. This resistance mechanism will be explored in NRAS mutant melanoma in Project 1 and across melanoma with resistance to anti-PD1 in Project 3. Reciprocally, Project 3 will seek to integrate the new concepts and models from Projects 1 and 2, given the likely immune effects of inducing these new forms of cell death. This collaborative research will require sharing the patient-derived tissues, model systems, and therapeutic regiments acquired and developed in each Project, facilitated by Cores B and C, and statistical design and support from Core A. 1


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 = $0 )
2026	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	5	12/2/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $2,478,520 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	5	7/3/2024	NON-COMPETING CONTINUATION	$2,478,520
														Subtotal = $2,478,520

Issue Date FY: 2023 ( Subtotal = $2,556,789 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	4	6/30/2023	NON-COMPETING CONTINUATION	$2,556,789
														Subtotal = $2,556,789

Issue Date FY: 2022 ( Subtotal = $2,556,789 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	3	8/30/2022	NON-COMPETING CONTINUATION	$2,556,789
														Subtotal = $2,556,789

Issue Date FY: 2021 ( Subtotal = $2,608,967 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	2	7/1/2021	NON-COMPETING CONTINUATION	$2,608,967
														Subtotal = $2,608,967

Issue Date FY: 2020 ( Subtotal = $2,574,738 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	1	9/11/2020	NEW	$2,574,738
														Subtotal = $2,574,738

Grand Total All Awards = $12,775,803

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Combination Therapies to Defeat Melanoma Resistance

Award Number: P01CA244118

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/11/2020

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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