Sunday, January 11, 2026 1/11/2026

Integrin-mediated mechanisms of prostate cancer progression

Award Number: R01CA224769
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/15/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Integrin-mediated mechanisms of prostate cancer progression - ABSTRACT Therapeutic approaches aimed at curing prostate cancer (PrCa) are only partially successful given the occurrence of highly metastatic resistant phenotypes that frequently develop in response to chemical castration of PrCa patients. Recently, we have, for the first time, described αvβ6, a surface receptor of the integrin family as a novel therapeutic target for PrCa treatment; this molecule is an ideal target since, unlike other integrins, it is found in different types of cancer but not in normal tissues. We have demonstrated unique properties of this molecule in PrCa that are not observed for other integrins: we have shown that αvβ6 promotes castrate- resistant prostate cancer (CRPC) via activation of JNK and androgen receptor (AR). Furthermore, we have shown that αvβ6 is found in cancer cell exosomes, is transferred from cancer cells to recipient cells by exosomes and remains active in the recipient cells. We also demonstrate that αvβ6 has profound effects on the microenvironment. Specifically, αvβ6 prevents induction of the Stat1/Mx1/2 signaling pathway in donor cancer cells, and their exosomes, and its down-regulation in cancer cell exosomes inhibits monocyte M2 polarization. Finally, we demonstrate that αvβ6 inhibition in vivo causes upregulation of the Stat1/MxA/B signaling pathway in cancer cells. Based on our highly rigorous mechanistic studies, we propose the following innovative hypothesis: αvβ6 expression affects the microenvironment by down-regulating Stat1/Mx1 levels in donor cells, and subsequently in cancer cell exosomes and recipient cells, thereby promoting monocyte differentiation, tumor growth, and cancer progression. Consequently, by down-regulating or inhibiting αvβ6 in cancer cells, increased Stat1/MxA/B levels in cells/ exosomes/ monocytes will be generated producing an anti-tumor effect. To test this hypothesis, we plan the following three specific aims. We will examine in vitro the role of αvβ6 integrin in regulating cancer cell - monocyte crosstalk (Aim 1), and analyze in vivo the functional role of the pathway mediated by exosomal αvβ6 and/or Stat1 in cancer progression (Aim 2) and characterize the αvβ6 integrin/Stat1 pathway in PrCa cells (Aim 3). Innovative approaches, highly purified exosomes and in vivo models will be used to test our hypothesis that transfer of integrins and their downstream effectors from cancer cells to other cells in the tumor microenvironment promotes CRPC. The study will be supported by a multidisciplinary team of investigators who have extensive and complementary expertise in all the required technologies. Based on our preliminary data on the αvβ6/Stat1 pathway and planned experimental design for this project, we expect that our study will elucidate new mechanisms that promote PrCa and validate new targets for PrCa therapeutic approaches.


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 = -$326 )
2026	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	5	12/2/2025	NON-COMPETING CONTINUATION	-$326
														Subtotal = -$326

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	5	8/12/2024	NON-COMPETING CONTINUATION	$0
2024	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	001	5	8/12/2024	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $356,342 )
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	001	5	8/15/2022	SUPPLEMENT FOR EXPANSION	$4,883
2022	2022	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	5	6/27/2022	NON-COMPETING CONTINUATION	$351,459
														Subtotal = $356,342

Issue Date FY: 2021 ( Subtotal = $421,110 )
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	001	4	6/30/2021	SUPPLEMENT FOR EXPANSION	$64,260
2021	2021	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	4	6/29/2021	NON-COMPETING CONTINUATION	$356,850
														Subtotal = $421,110

Issue Date FY: 2020 ( Subtotal = $536,092 )
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	3	6/18/2020	NON-COMPETING CONTINUATION	$356,850
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Biology Research	002	3	9/8/2020	SUPPLEMENT FOR EXPANSION	$59,296
2020	2020	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	001	3	8/24/2020	NON-COMPETING CONTINUATION	$119,946
														Subtotal = $536,092

Issue Date FY: 2019 ( Subtotal = $346,194 )
2019	2019	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	2	7/1/2019	NON-COMPETING CONTINUATION	$346,194
														Subtotal = $346,194

Issue Date FY: 2018 ( Subtotal = $369,820 )
2018	2018	THOMAS JEFFERSON UNIVERSITY	1020 WALNUT ST STE 1	PHILADELPHIA	PA	19107	PHILADELPHIA	USA	Cancer Detection and Diagnosis Research	000	1	7/12/2018	NEW	$369,820
														Subtotal = $369,820

Grand Total All Awards = $2,029,232

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Integrin-mediated mechanisms of prostate cancer progression

Award Number: R01CA224769

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/15/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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