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The function of the PRMT5 methylosome in MTAP deleted cancers

Award Number: R01CA233626
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2030

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The function of the PRMT5 methylosome in MTAP deleted cancers - PROJECT SUMMARY The methylthioadenosine phosphorylase gene (MTAP) is frequently co-deleted with CDKN2A, occurring in 25-50% of cancers of the pancreas, esophagus, and lung. We discovered that MTAP deletion leads to selective dependency of cancer cells on PRMT5, a discovery that led to multiple therapeutic programs. MTAP loss leads to high levels of its substrate methylthioadenosine (MTA), which competes with S-adenosylmethionine (SAM), thus acting as a specific inhibitor of PRMT5. We first proposed that MTA-cooperative PRMT5 inhibitors (MTAC- P5i’s) would be needed to exploit this synthetic lethality. New MTAC-P5i’s are showing significant tumor responses in MTAP/CDKN2A-deleted cancers in phase I clinical trials, and MTAC-P5i’s are well-tolerated without evidence of myelosuppression. This proposal will build on strong preliminary data and will leverage state-of-the- art technologies and model systems to define mechanisms of tumor cell-intrinsic and -extrinsic sensitivity and resistance to MTAC-P5i therapy, ultimately informing combination therapy strategies to advance in clinical trials. Despite promising early clinical data with MTAC-P5i’s, resistance emerges and will require new therapeutic combinations. In Aim 1, we will deploy novel functional genomic approaches, including a dual-targeting CRISPR library disrupting single genes and closely related paralog pairs, to define the tumor cell-intrinsic mechanisms of sensitivity and resistance to MTAC-P5i. We will discover genetic and therapeutic perturbations that augment or blunt response to MTAC-P5i’s. We will also conduct in vivo validation studies testing MRTX1719 combinations, furthering the validation of our preliminary work with RAS pathway inhibitors and expanding to include CDK4/6 or MAT2A inhibitors. Lastly, we will investigate genetic mechanisms of acquired resistance to MTAC-P5i’s through genomic characterization of in vivo PDX models. MTAP-deletion also results in the excretion of the metabolite MTA into the tumor microenvironment (TME). MTA is known to mediate an immunosuppressive effect; however, the full impact of MTA on cellular components of the TME and its implications for combination therapy remain unknown. In Aim 2, we will dissect the role of MTA and MTAC-P5i in remodeling the TME and examine combinations of MTAC-P5i and RAS pathway inhibitors in using novel Mtap-deficient immunocompetent orthotopic transplant models of pancreatic ductal adenocarcinoma (PDAC). We will utilize multi-modal approaches to elucidate the impact of MTAP deletion and MTAC-P5i’s on the TME. We will also leverage these models to examine the combinatorial efficacy of MTAC- P5i with KRASG12D or B/CRAF inhibition and immune checkpoint blockade. Lastly, we will use in vitro isogenic model systems to examine the influence of MTA and MTAC-P5i on T-cell viability and activity. Collectively, these studies will address challenges to improve the efficacy of MTAC-P5i therapy, including defining mechanisms of resistance, elucidating the role of MTA and MTAC-P5i in remodeling the TME, and credentialing top combination therapy strategies, with the eventual goal of informing next-generation clinical trial development for patients.


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 = $472,119 )
2025	2025	THE BROAD INSTITUTE, INC	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Treatment Research	000	6	9/17/2025	COMPETING CONTINUATION	$472,119
														Subtotal = $472,119

Issue Date FY: 2023 ( Subtotal = $380,377 )
2023	2023	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Treatment Research	000	5	8/4/2023	NON-COMPETING CONTINUATION	$380,377
														Subtotal = $380,377

Issue Date FY: 2022 ( Subtotal = $380,377 )
2022	2022	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Treatment Research	000	4	6/27/2022	NON-COMPETING CONTINUATION	$380,377
														Subtotal = $380,377

Issue Date FY: 2021 ( Subtotal = $388,141 )
2021	2021	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Treatment Research	000	3	7/1/2021	NON-COMPETING CONTINUATION	$388,141
														Subtotal = $388,141

Issue Date FY: 2020 ( Subtotal = $435,438 )
2020	2020	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Treatment Research	000	2	7/1/2020	NON-COMPETING CONTINUATION	$435,438
														Subtotal = $435,438

Issue Date FY: 2019 ( Subtotal = $432,036 )
2019	2019	BROAD INSTITUTE, INC., THE	415 MAIN ST	CAMBRIDGE	MA	02142	MIDDLESEX	USA	Cancer Treatment Research	000	1	7/1/2019	NEW	$432,036
														Subtotal = $432,036

Grand Total All Awards = $2,488,488

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The function of the PRMT5 methylosome in MTAP deleted cancers

Award Number: R01CA233626

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2030

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