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Combined inhibition of ATR and p110β as Therapy in PTEN-deficient Prostate Cancer

Award Number: R21CA288931
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2024
PERIOD OF PERFORMANCE END DATE: 08/31/2026

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Combined inhibition of ATR and p110β as Therapy in PTEN-deficient Prostate Cancer - Project Summary/Abstract Given the high mortality of castration-resistant prostate cancer (CRPC) as a result of relapse after androgen deprivation therapy (ADT), novel treatment strategies are urgently needed. Tumor suppressor gene- phosphatase and tensin homolog ( PTEN) is mutated in approximately 20% of primary prostate cancers, and in as many as 40~60% of CRPC. In addition to activation of PI3K oncogenic signaling pathway, loss of PTEN is also associated with cytokine and chemokine signaling that creates an immunosuppressive microenvironment. Both defects in antigen presentation in tumor cells and the immunosuppressive tumor microenvironment (TME) have been implicated in CRPC progression after ADT and therapeutic resistance in prostate cancer in the clinic. Genetic or pharmacologic inactivation of β isoform of PI3K (p110β) in PTEN-deficient prostate cancer has been reported to significantly inhibit tumor growth and progression. Ataxia telangiectasia and Rad3-related (ATR) exhibits essential functions in controlling DNA replication stress and DNA damage response in cancer cells. PTEN-deficient cells have been reported to be more sensitive to ATR inhibition. PI3Kβ is also functionally associated with DNA damage response and genomic integrity in tumor growth. By using a syngeneic genetically engineered mouse model of CRPC driven by co-deletion of PTEN and TP53 (PP-CRPC), we found that addition of p110β inhibitor significantly reduces the viability of ATR inhibitor-treated PP-CRPC cells. Moreover, our preliminary data show that inhibition of p110β or ATR alone significantly increases MHC class I antigen presentation in mouse or human CRPC cells. Based on these novel preliminary data, we hypothesize that p110β inhibitor in combination with ATR inhibitor will show promising anti-tumor activity in PTEN-deficient CRPC via inducing cell death in cancer cells and anti-tumor immunity in the tumor microenvironment. We also hypothesize that inhibition of p110β will increase DNA replication stress and sensitize PTEN-deficient CRPC cells to ATR inhibition. In this study, we will 1) evaluate the therapeutic efficacy and antitumor immune responses of combined ATR inhibition and p110β inhibition i n syngeneic PTEN-deficient CRPC mouse models; 2) investigate the molecular mechanisms of the combined effect of ATR inhibitor and p110β inhibitor in replication stress and DNA damage-induced cell death in PTEN-deficient CRPC cells. Our study will not only provide fundamental information for translational research of p110β inhibitors and ATR inhibitors in cancer treatment, but also provide a novel treatment strategy for patients with PTEN-deficient advanced CRPC.


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	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Treatment Research	000	2	2/2/2026	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2025 ( Subtotal = $243,334 )
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Treatment Research	001	2	5/22/2025	NON-COMPETING CONTINUATION	$24,334
2025	2025	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Treatment Research	000	2	3/3/2025	NON-COMPETING CONTINUATION	$219,000
														Subtotal = $243,334

Issue Date FY: 2024 ( Subtotal = $202,778 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Treatment Research	000	1	2/22/2024	NEW	$202,778
														Subtotal = $202,778

Grand Total All Awards = $446,112

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Combined inhibition of ATR and p110β as Therapy in PTEN-deficient Prostate Cancer

Award Number: R21CA288931

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2024

PERIOD OF PERFORMANCE END DATE: 08/31/2026

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