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Novel Approaches Targeting B7-H3 in Castration-resistant Prostate Cancer

Award Number: R01CA275990
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2023
PERIOD OF PERFORMANCE END DATE: 12/31/2027

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Novel Approaches Targeting B7-H3 in Castration-resistant Prostate Cancer - ABSTRACT More than 60% of metastatic castration-resistant prostate cancers (CRPC) contain PTEN and TP53 gene deletions and mutations. To date, there are limited treatment options for this molecular subtype. The overall objective of this application is to elucidate the complex role of B7-H3 signaling in prostate cancer (PCa) as well as develop biomarker-driven B7-H3 targeted therapy for CRPC. Our preliminary studies demonstrated that PTEN/TP53 defects induce B7-H3 overexpression and that depletion of B7-H3 in cancer cells remarkably impaired progression of PTEN/p53-deficient PCa in vivo. Mass cytometry analysis revealed that B7-H3 signaling is involved in modulating immunosuppressive myeloid cells in the PCa tumor microenvironment (TME). Here, the central hypothesis is that B7-H3 signaling contributes to the progression of PCa containing PTEN/p53 deficiencies and plays a key role in reprogramming immunosuppressive myeloid cells in the PCa TME. The central hypothesis will be tested by pursuing the following specific aims. Aim 1. Elucidate B7-H3’s impact on progression of advanced PCa containing PTEN/TP53 loss. The hypothesis in this aim is that B7-H3 plays a key role in PCa progression and resistance to ADT and that PTEN/TP53 defects render CRPC more responsive to B7-H3 targeted therapy. To this end, we have generated a novel GEMM with prostate-specific co-deletion of Pten/Trp53/Cd276. This state-of-the-art spontaneous GEMM provides a unique tool to dissect the role of B7-H3 signaling in PCa development and therapeutic resistance. Mechanistic studies will illuminate how PTEN and p53 pathways control B7-H3 expression. Clinical relevance among B7-H3 expression, PTEN/TP53 status, and disease progression will be assessed in human CRPCs. B7-H3 targeted therapies will also be tested in various preclinical models of metastatic CRPC containing PTEN/TP53 loss. Aim 2. Understand how B7-H3 signaling modulates immunosuppressive myeloid cells in CRPC. The hypothesis is that B7-H3 signaling contributes to the reprogramming of myeloid cells in the PCa TME. Single-cell transcriptomics analysis will be performed in above GEMMs. Functional studies will address how B7-H3 signaling mediates the crosstalk between cancer cells and immunosuppressive myeloid cells. B7-H3 receptor(s) and the downstream signaling pathway(s) in myeloid cells will also be characterized. Finally, the therapeutic potential of co-targeting B7-H3 and immunosuppressive myeloid cells will be evaluated in preclinical models of CRPC. These studies are expected to have significant positive impacts, including advancing the understanding of B7-H3 biology in cancers and providing a compelling rationale for the use of PTEN and TP53 defects as molecular biomarkers for predicting response to B7-H3-targeted therapy for patients with CRPC. The proposed research will also establish, for the first time, the role of B7-H3 signaling in reprogramming myeloid cells in the TME and develop effective combinatorial immunotherapy targeting B7-H3.


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 = $588,065 )
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	4	12/18/2025	NON-COMPETING CONTINUATION	$529,259
2026	2026	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	4	4/16/2026	NON-COMPETING CONTINUATION	$58,806
														Subtotal = $588,065

Issue Date FY: 2025 ( Subtotal = $588,065 )
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	3	6/4/2025	NON-COMPETING CONTINUATION	$58,806
2025	2025	THE UNIVERISTY OF TEXAS M.D. ANDERSON CANCER CENTER	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	3	12/10/2024	NON-COMPETING CONTINUATION	$529,259
														Subtotal = $588,065

Issue Date FY: 2024 ( Subtotal = $558,663 )
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	001	2	4/16/2024	NON-COMPETING CONTINUATION	$29,404
2024	2024	THE UNIVERISTY OF TEXAS MD ANDERSON CANCER CENTER, A COMPONENT OF THE UNIVERISTY OF TEXAS SYSTEM	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	2	12/15/2023	NON-COMPETING CONTINUATION	$529,259
														Subtotal = $558,663

Issue Date FY: 2023 ( Subtotal = $588,065 )
2023	2023	UNIVERSITY OF TEXAS M. D. ANDERSON CANCER CENTER, THE	1515 HOLCOMBE BLVD	HOUSTON	TX	77030	HARRIS	USA	Cancer Biology Research	000	1	12/16/2022	NEW	$588,065
														Subtotal = $588,065

Grand Total All Awards = $2,322,858

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Novel Approaches Targeting B7-H3 in Castration-resistant Prostate Cancer

Award Number: R01CA275990

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2023

PERIOD OF PERFORMANCE END DATE: 12/31/2027

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