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Protein kinase C signaling in prostate cancer health disparities

Award Number: R01CA276082
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/08/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Protein kinase C signaling in prostate cancer health disparities - ABSTRACT Prostate cancer (PCa), the second leading cause of cancer-related deaths among men in the US, disproportionally affects men of African American (AA) descent, who exhibit greater incidence, faster disease progression and higher rate of mortality than men of European descent (EA). AA men are more likely to present high-grade disease and distant metastasis at the time of diagnosis. The drivers of this disparity are multifactorial, and include socioeconomic, lifestyle and biological factors. Current evidence suggests genetic alterations - such as changes in oncogenic and tumor suppressive genes associated with PCa progression - and the presence of a more inflammatory tumor microenvironment (TME) in prostate tumors from men of African descent as major underlying causes of this racial disparity. However, there is still a limited understanding of the molecular foundations behind the racial differences in PCa. Here, we identified the diacylglycerol-regulated kinase PKCa as a potential contributor towards racial disparities in PCa. We found PKCa to be aberrantly overexpressed in aggressive PCa cell lines as well as in human PCa. Interestingly, silencing PKCa expression from PCa cells impairs their invasive capacity as well as its ability to form tumors in mice. An in-depth RNA-Seq transcriptome analysis integrated with existing database inquires established PKCa as a crucial determinant for the expression of cytokines known to be dysregulated in prostate tumors from AA men. Most remarkably, database analysis suggests higher PKCa expression in AA relative to EA prostate tumors. This led us to hypothesize that excessive activation of PKCa signaling may contribute to racial disparities in PCa. In Aim 1 we will take advantage of a large collection of primary and metastatic human PCa tumors both from AA and EA men to test the hypothesis that there is disproportionate PKCa expression and/or activation in AA PCa. We will establish potential correlations with Gleason score, disease recurrence and metastatic disease in the available cohorts of AA and EA prostate tumors. In Aim 2 we will use both genetically engineered (PKCa-null/TRAMP mice) and syngeneic models (orthotopic implantation of TRAMP-derived PCa cells) towards the goal of establishing the in vivo functional relevance of PKCa in prostate tumorigenesis and metastasis. We will authenticate the findings in vivo using a pharmacological (PKCa inhibitor) approach. In Aim 3 we will determine the relevance of prostate cancer cell PKCa in the control of the tumor immune landscape and gene expression. We will pursue a thorough characterization of immune cell populations and cytokine expression in mouse prostate tumors upon inducible silencing of PKCa. This will provide a comprehensive perspective on how tumor cell PKCa contributes to the generation of a pro-inflammatory tumorigenic state and an immunosuppressive landscape that is a hallmark of PCa in AA men. In addition to revealing a novel biomarker for PCa progression and potential therapeutic target, our studies should provide exceptionally valuable information on the pathways leading to racial disparities in PCa and help strategizing novel therapeutic avenues.


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 = $583,194 )
2025	2025	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	002	3	5/13/2025	NON-COMPETING CONTINUATION	$583,194
2025	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	001	2	2/27/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$87,137
2025	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	2/27/2025	NEW	-$87,137
														Subtotal = $583,194

Issue Date FY: 2024 ( Subtotal = $576,595 )
2024	2024	UNIVERSITY OF MIAMI	1320 S DIXIE HWY STE 1200	CORAL GABLES	FL	33146	MIAMI-DADE	USA	Cancer Biology Research	001	2	9/5/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$576,595
2024	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	9/5/2024	NEW	$0
														Subtotal = $576,595

Issue Date FY: 2023 ( Subtotal = $488,027 )
2023	2023	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST STE 440A	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	1	6/8/2023	NEW	$488,027
														Subtotal = $488,027

Grand Total All Awards = $1,647,816

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Protein kinase C signaling in prostate cancer health disparities

Award Number: R01CA276082

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/08/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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