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Multidimensional analyses to improve PSMA-RPT efficacy in mCRPC

Award Number: R01CA279094
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/12/2023
PERIOD OF PERFORMANCE END DATE: 03/31/2028

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Multidimensional analyses to improve PSMA-RPT efficacy in mCRPC - Summary/Abstract While prostate-specific membrane antigen-targeted radiopharmaceutical therapy (PSMA-RPT) improves the survival of metastatic castration-resistant prostate cancer (mCRPC) patients, response rates remain suboptimal, and relapses invariably occur in all patients. Improving therapeutic efficacy requires a better understanding of the genetic, molecular, and immunological determinants of tumor responses to PSMA RPT. To identify such determinants we (i) performed dosimetry studies to optimize 177Lu-PSMA-RPT activity in prostate cancer (PCa) models; (ii) conducted global phosphoproteomic analyses of tumors from PSMA-RPT- treated mice and revealed the upregulation of DNA damage response/repair and TP53 pathways; (iii) showed that wild type TP53 plays an important role in mediating responses to RPT in mice; and (iv) investigated the impact of PSMA-RPT on the tumor immune microenvironment and demonstrated that PSMA-RPT synergizes with pharmacological activators of the cyclic GMP–AMP synthase (cGAS)/Stimulator of Interferon genes (STING) pathway, a cytosolic DNA sensing machinery that links DNA damage with the induction of innate immune responses via type I interferon (IFN) signaling. Relatedly, data in the literature indicate that mutant TP53, which occurs frequently in mCRPC, interferes with the function of the cGAS/STING/IFN pathway thereby decreasing tumor immunogenicity. Collectively, these findings led us to hypothesize that (i) 177Lu- PSMA-RPT triggers tumor TP53 mutational status-dependent tumor and immune cell signaling alterations in mCRPC; (ii) profiling these alterations will identify new determinants of response to PSMA-RPT; and (iii) targeting these determinants will enhance responses to PSMA-RPT. We will test these hypotheses via three Specific Aims leveraging an integrated platform for systematic profiling of RPT-induced transcriptional, signaling, and immunological alterations. In Aim 1, we will identify RPT-induced signaling alterations in the tumor cell compartment of human PSMA-expressing PCa models and test the hypothesis that mutant TP53 impairs responses to PSMA-RPT. In Aim 2, we will employ murine PCa models with wild-type or mutated TP53 to investigate how tumor TP53 status impacts RPT responses and tumor immunogenicity in immunocompetent mice. We will test the hypothesis that mutant TP53 interferes with cGAS/STING/IFN signaling in RPT-treated tumors and reduces tumor immunogenicity. In Aim 3, we will develop novel combination therapies that enhance or restore the cGAS/STING/IFN pathway in the mCRPC immune tumor microenvironment and improve the magnitude and durability of RPT responses via increased tumor immunogenicity. Successful completion of these aims will identify new connections between mCRPC TP53 mutational status, cytosolic DNA sensing mechanisms, and tumor immunogenicity that can be leveraged to increase the efficacy of RPT against mCRPC through rationally designed and clinically applicable combination 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: 2026 ( Subtotal = $438,529 )
2026	2026	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	4	6/26/2026	NON-COMPETING CONTINUATION	$438,529
														Subtotal = $438,529

Issue Date FY: 2025 ( Subtotal = $584,235 )
2025	2025	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	3	6/24/2025	NON-COMPETING CONTINUATION	$584,235
														Subtotal = $584,235

Issue Date FY: 2024 ( Subtotal = $567,087 )
2024	2024	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	2	6/20/2024	NON-COMPETING CONTINUATION	$567,087
														Subtotal = $567,087

Issue Date FY: 2023 ( Subtotal = $528,393 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Treatment Research	000	1	7/12/2023	NEW	$528,393
														Subtotal = $528,393

Grand Total All Awards = $2,118,244

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Multidimensional analyses to improve PSMA-RPT efficacy in mCRPC

Award Number: R01CA279094

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/12/2023

PERIOD OF PERFORMANCE END DATE: 03/31/2028

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