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Preventing MAPK inhibitor resistance in melanoma by targeting genomic instability and immune resistance

Award Number: R01CA176111
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/04/2013
PERIOD OF PERFORMANCE END DATE: 06/30/2029

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Preventing MAPK inhibitor resistance in melanoma by targeting genomic instability and immune resistance - PROJECT SUMMARY In the treatment of BRAFV600MUT melanoma, acquired resistance to MAPK inhibitor (MAPKi) limits its survival benefits. Currently, MAPKi therapy is unavailable to patients with non-BRAFV600MUT melanoma. To improve MAPKi therapy and to extend its application to more patients, we propose a project to develop two general concepts to render MAPKi therapy more effective. Both concepts aim to prevent acquired MAPKi resistance by targeting processes that are operative early on MAPKi therapy and that enable melanoma persisters to undergo clonal evolution. In prior publications, we and others have shown that the selective pressure of MAPKi elicits (i) a new round of genomic instability, leading to clonal diversification and selective expansion of clones that drive acquired resistance and (ii) a new round of immune editing and hence immune resistance, leading to selective expansion of clones that evade antitumor immunity (in particular cytotoxic T cells). We hypothesize that therapeutic strategies that address these adaptive mechanisms in residual tumor cells on MAPKi therapy can potentially prevent the seeds of acquired resistance. We expect that preventive approaches such as these, combined with the more durable efficacy of antitumor immunity, should be more effective than conventional approaches to target specific vulnerabilities of acquired resistance, due to extensive tumor heterogeneity and clonal evolution resulting from disease progression. In Aim 1, we build on our recent study showing that genomic instability such as chromothripsis gives rise to amplicons that are selected by MAPKi to cause acquired resistance. These amplicons may be intrachromosomal or extrachromosomal, the latter as circular ecDNAs. This finding led to further discovery that a combination to block these mechanisms of genomic instability may prevent acquired resistance and the design of a trial testing this combination as targeted therapy for NRASMUT melanoma. We hypothesize that the mechanisms by which MAPKi elicits de novo genomic instability represent combinatorial targets to prevent acquired resistance. These mechanisms involve the partial rupture of primary and micronuclear membranes, chromosome mis-segregation and DNA-damaging proteins that aberrantly access normally protected chromosomal DNAs. In Aim 2, we build on our recent published and unpublished studies showing that innate/adaptive immune resistance arises in persisters early on MAPKi or immune checkpoint blockade (ICB) therapy, which results in PD-L1 accumulation on the tumor surface. To diminish immune resistance, we identified a tool compound AK087 to degrade surface PD-L1, thereby improving the efficacy of MAPKi (and ICB) therapy in immune-competent murine tumor models. Here, we will dissect the mechanisms of action of AK087 to guide further the rational development of PD-L1 degraders as a general combinatorial strategy to improve the efficacy current melanoma therapies.


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: 2025 ( Subtotal = $393,750 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	002	12	6/24/2025	NON-COMPETING CONTINUATION	$393,750
2025	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	001	11	2/28/2025	COMPETING CONTINUATION	$481
2025	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	10	2/28/2025	NON-COMPETING CONTINUATION	-$481
														Subtotal = $393,750

Issue Date FY: 2024 ( Subtotal = $393,750 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	11	9/4/2024	COMPETING CONTINUATION	$393,750
														Subtotal = $393,750

Issue Date FY: 2023 ( Subtotal = $363,090 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	10	6/21/2023	NON-COMPETING CONTINUATION	$363,090
														Subtotal = $363,090

Issue Date FY: 2022 ( Subtotal = $363,090 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	9	7/28/2022	NON-COMPETING CONTINUATION	$363,090
														Subtotal = $363,090

Issue Date FY: 2021 ( Subtotal = $370,500 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	8	6/28/2021	NON-COMPETING CONTINUATION	$370,500
														Subtotal = $370,500

Issue Date FY: 2020 ( Subtotal = $370,500 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	002	7	6/11/2020	NON-COMPETING CONTINUATION	$370,500
2020	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	001	6	12/3/2019	COMPETING CONTINUATION	$481
2020	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	5	12/3/2019	NON-COMPETING CONTINUATION	-$481
														Subtotal = $370,500

Issue Date FY: 2019 ( Subtotal = $370,500 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	6	4/10/2019	COMPETING CONTINUATION	$370,500
														Subtotal = $370,500

Issue Date FY: 2017 ( Subtotal = $319,550 )
2017	2017	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	002	5	6/22/2017	NON-COMPETING CONTINUATION	$319,550
2017	2016	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	001	4	11/17/2016	EXTENSION WITH OR WITHOUT FUNDS	$71,660
2017	2015	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	3	11/17/2016	NON-COMPETING CONTINUATION	-$71,660
														Subtotal = $319,550

Issue Date FY: 2016 ( Subtotal = $319,550 )
2016	2016	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	4	6/1/2016	EXTENSION WITH OR WITHOUT FUNDS	$319,550
														Subtotal = $319,550

Issue Date FY: 2015 ( Subtotal = $319,550 )
2015	2015	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	3	6/12/2015	NON-COMPETING CONTINUATION	$319,550
														Subtotal = $319,550

Issue Date FY: 2014 ( Subtotal = $309,964 )
2014	2014	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	2	7/2/2014	NON-COMPETING CONTINUATION	$309,964
														Subtotal = $309,964

Issue Date FY: 2013 ( Subtotal = $319,550 )
2013	2013	UNIVERSITY OF CALIFORNIA-LOS ANGELES, BOARD OF REGENTS	11000 KINROSS AVENUE	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Treatment Research	000	1	8/7/2013	NEW	$319,550
														Subtotal = $319,550

Grand Total All Awards = $4,213,344

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Preventing MAPK inhibitor resistance in melanoma by targeting genomic instability and immune resistance

Award Number: R01CA176111

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/04/2013

PERIOD OF PERFORMANCE END DATE: 06/30/2029

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