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Androgen Deprivation Activates Wnt/Beta-Catenin Signaling in Prostate Cancer

Award Number: R01CA226285
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2018
PERIOD OF PERFORMANCE END DATE: 12/31/2024

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Androgen Deprivation Activates Wnt/Beta-Catenin Signaling in Prostate Cancer - SUMMARY Androgen deprivation therapy has been the gold standard for the treatment of advanced prostate cancer (PCa) since the 1960s. Patients initially respond well to the treatment resulting in tumor regression, but ultimately progress to castrate-resistant PCa for which there is no cure. New anti-androgens have shown significant improvement in treating PCa patients who failed androgen deprivation therapy. However, even PCa patients on enzalutamide (the most potent anti-androgen therapy), eventually progress to castrate-resistant PCa. Moreover, once PCa becomes castrate-resistant, an aggressive neuroendocrine (NE) phenotype ensue with high morbidity, with only an average survival of less than 1.5 years. There are currently no effective treatments against PCa with a prominent NE phenotype. Therefore, identifying the mechanism(s) through which NE phenotype arises as consequence to anti-androgen therapies is critical for the development of novel therapeutics against PCa. The Wnt/beta-Catenin signaling pathway is prevalent in advanced PCa. We previously showed that activation of Wnt/beta-Catenin signaling promotes the development of castrate- resistant PCa with an increased NE phenotype, thus linking the active Wnt/beta-Catenin signaling with castrate-resistant progression and the emergence of NE phenotype in PCa. Consistent with this, we corroborated that the Wnt/beta-Catenin pathway is active in the NEPCa. Androgen deprivation has been shown to accelerate the emergence of the NE phenotype in PCa. Our preliminary data demonstrated that androgen deprivation upregulated Wnt7a, a Wnt ligand that can activate Wnt/beta-Catenin signaling. Our data also indicated that androgen deprivation upregulated Dkk1, an endogenous secretory inhibitor of the Wnt/beta- Catenin signaling, in normal prostates but not in PCa. Based on these observations, we hypothesize that androgen deprivation activates Wnt/beta-Catenin signaling to promote castrate-resistant progression and NE differentiation of PCa. This hypothesis will be tested by the following Specific Aims: Aim 1: To determine how androgen deprivation activates Wnt/beta-Catenin signaling in PCa. Aim 2: To determine the mechanism(s) through which androgen deprivation modulates Wnt/beta-Catenin signaling by regulating stromal/epithelial interaction. Aim 3: To determine whether blocking the Wnt/beta-Catenin pathway (via inducible expression of DKK1 and pharmacological inhibitors) suppresses NEPCa.


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 = -$5,548 )
2025	2022	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	000	5	5/5/2025	NON-COMPETING CONTINUATION	-$5,548
														Subtotal = -$5,548

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	000	5	7/3/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $325,054 )
2022	2022	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	000	5	6/23/2022	NON-COMPETING CONTINUATION	$325,054
														Subtotal = $325,054

Issue Date FY: 2021 ( Subtotal = $331,688 )
2021	2021	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	000	4	6/23/2021	NON-COMPETING CONTINUATION	$331,688
														Subtotal = $331,688

Issue Date FY: 2020 ( Subtotal = $331,688 )
2020	2020	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	000	3	6/25/2020	NON-COMPETING CONTINUATION	$331,688
														Subtotal = $331,688

Issue Date FY: 2019 ( Subtotal = $321,736 )
2019	2019	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	000	2	6/27/2019	NON-COMPETING CONTINUATION	$321,736
														Subtotal = $321,736

Issue Date FY: 2018 ( Subtotal = $331,688 )
2018	2018	LOUISIANA STATE UNIVERSITY	1501 KINGS HWY	SHREVEPORT	LA	71103	CADDO	USA	Cancer Biology Research	000	1	6/27/2018	NEW	$331,688
														Subtotal = $331,688

Grand Total All Awards = $1,636,306

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Androgen Deprivation Activates Wnt/Beta-Catenin Signaling in Prostate Cancer

Award Number: R01CA226285

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2018

PERIOD OF PERFORMANCE END DATE: 12/31/2024

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