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Functional Consequences of Racially Associated Ephrin Alterations on the Prostate Tumor Microenvironment

Award Number: R01CA242920
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/03/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Functional Consequences of Racially Associated Ephrin Alterations on the Prostate Tumor Microenvironment - Project Summary Prostate cancer (PCa) incidence and mortality remain significantly higher in African American (AA) men compared to Caucasians (CA). Although socioeconomic factors may contribute to such differences, recent studies suggest that biological factors could potentially explain racial disparities (RD) in PCa. A few high- penetrance genes (HPG) have been found to predispose to high risk of PCa in AA men. These include EphB2 mutations. EphB2 is a tyrosine kinase (RTK) receptor that binds to the Ephrin ligand and initiates bidirectional signals that affect both receptor (forward signaling) and Ephrin-expressing cells (reverse signaling). Our preliminary observations suggest a potential supportive role of Ephrin signaling activation within stromal cells in the tumor microenvironment (TME) due to the pathogenicity of these EphB2 genetic alterations. However the functional consequences of EphB2 alterations on prostate cancer cell biology have not been experimentally validated. To better understand the intrinsic mechanism(s) responsible for these pathogenic effects we hypothesize that EphB2 alterations commonly seen in AA men may induce aberrant “forward signaling” reducing its tumor suppressor function in cancer cells and abnormal “reverse signaling” increasing the activation of stromal in the TME, overall resulting in support for PCa progression. This proposal seeks to understand the downstream molecular effectors of disrupted Eph-Ephrin signaling in AA men in both tissue compartments (epithelium and stroma) on PCa progression. The long-term goal is to identify novel targetable molecules within the cancer and/or stromal compartment that can be used to improve diagnosis and treatment of patients at high-risk of developing aggressive PCa disease in AA men. Three complementary areas will be investigated: 1. Determine the functional effects of racial EphB2 alterations on PCa progression. We will study the functional consequence of common EphB2 alterations seen in AA men with PCa, on proliferation and motility of PCa cells in vitro and in vivo. The role of EphB2 in PCa cell biology is unknown. 2. Determine the role of Ephrin reverse signaling on CAF activation in the TME of AA men. We observed increased expression of EphB2 ligands in the TME of AA compared to CA men suggesting a dysfunctional regulation of Ephrin-reverse signaling. In addition we observed that prostate stromal cell from AA patients with PCa induce increased proliferation and motility of PCa cell lines in vitro and in vivo. 3. Evaluate the utility of targeting the Eph-Ephrin signaling to inhibit PCa progression. It has been shown in experimental models that normalizing Eph-Ephrin signaling can reduce colon cancer progression. The utility in PCa has not been previously studied. Using an in vivo PCa model, we will assess the feasibility of targeting Eph-Ephrin signaling frequently altered in AA men to inhibit PCa tumorigenesis.


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 = $0 )
2025	2022	ENDEAVOR HEALTH CLINICAL OPERATIONS	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Biology Research	001	4	1/14/2025	NON-COMPETING CONTINUATION	-$155,171
2025	2022	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	002	5	1/14/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$193,674
2025	2021	ENDEAVOR HEALTH CLINICAL OPERATIONS	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Biology Research	000	3	1/14/2025	NON-COMPETING CONTINUATION	-$38,503
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $325,771 )
2024	2024	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	000	6	6/28/2024	NON-COMPETING CONTINUATION	$325,771
														Subtotal = $325,771

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2022	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	001	5	8/23/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$212,472
2023	2022	NORTHSHORE UNIVERSITY HEALTHSYSTEM	SUITE 301	EVANSTON	IL	60201	COOK	USA	Cancer Biology Research	000	4	8/23/2023	NON-COMPETING CONTINUATION	-$212,472
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $367,643 )
2022	2022	NORTHSHORE UNIVERSITY HEALTHSYSTEM	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Biology Research	000	4	7/25/2022	NON-COMPETING CONTINUATION	$367,643
														Subtotal = $367,643

Issue Date FY: 2021 ( Subtotal = $375,137 )
2021	2021	NORTHSHORE UNIVERSITY HEALTHSYSTEM	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Biology Research	000	3	7/5/2021	NON-COMPETING CONTINUATION	$375,137
														Subtotal = $375,137

Issue Date FY: 2020 ( Subtotal = $375,127 )
2020	2020	NORTHSHORE UNIVERSITY HEALTHSYSTEM	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Biology Research	000	2	7/1/2020	NON-COMPETING CONTINUATION	$375,127
														Subtotal = $375,127

Issue Date FY: 2019 ( Subtotal = $375,117 )
2019	2019	NORTHSHORE UNIVERSITY HEALTHSYSTEM	1301 CENTRAL ST	EVANSTON	IL	60201	COOK	USA	Cancer Biology Research	000	1	7/3/2019	NEW	$375,117
														Subtotal = $375,117

Grand Total All Awards = $1,818,795

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Functional Consequences of Racially Associated Ephrin Alterations on the Prostate Tumor Microenvironment

Award Number: R01CA242920

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/03/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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