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Androgen signaling and sterol metabolism in metastatic prostate cancer: Functional and therapeutic implication

Award Number: R15CA252997
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2025

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Androgen signaling and sterol metabolism in metastatic prostate cancer: Functional and therapeutic implication - Abstract Prostate cancer (PCa) is the most commonly diagnosed cancer in men and the second leading cause of cancer-related deaths in the USA. Relapsed androgen signaling and intratumoral sterol biosynthesis are hallmarks of castration-resistant PCa (CRPC). PCa growth and proliferation depend on androgen signaling by the Androgen Receptor (AR). Targeting the androgen synthesis pathways and transactivation function of AR is a primary therapeutic approach to treat PCa. The progression of PCa from castration-sensitive to the castration-resistant stage (CRPC) depends on the failure of androgen signaling antagonists and the dysregulation of AR-centric molecular mechanisms in a high percentage of patients. Recent studies show that microRNAs (miRNAs) exert post-transcriptional regulation of gene expression by targeting oncogenes and performing tumor-suppressive functions in various cancers, including PCa. Scientific premise: The fundamental discovery motivating the proposed study is that miR-149-5p targets the expression of two major transcription factors AR and sterol regulatory element-binding transcription factor 1 (SREBF1), both are druggable targets and are implicated in CRPC. Our central hypothesis entails that miR-149-5p post-transcriptionally downregulates AR and SREBF1, and inactivation of miR-149-5p expression during the prostate carcinogenesis leads to the upregulation of androgen signaling and sterol biosynthesis, which promotes CRPC. We will test our hypothesis by pursuing three integrated Specific Aims. In aim 1 we will test miR-149-5p anti-proliferation and anti-oncogenic function in PCa cells, in Aim 2, we will define molecular mechanisms which negatively affects the maturation of miR-149-5p and in the aim 3, we will test the therapeutic and prognostic value of miR-149-5p. Significance: The study will provide a tumor-suppressor role of miR-149-5p in CRPC. The innovative research approaches the disease from a novel miRNA-mediated control of the androgen signaling and intratumoral sterol biosynthesis pathways in particular testosterone metabolism by directly co-targeting AR and SREBF1, and both are druggable targets in CRPC. This study has the potential to test for the first time co-targeting of primary PCa promoting transcription factors and a new paradigm for improved patient therapies by identifying the significant key regulators of androgen signaling and sterol biosynthesis pathways.


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 = -$643 )
2026	2021	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	000	1	12/8/2025	NEW	-$643
														Subtotal = -$643

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2021	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	000	1	9/4/2024	NEW	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $412,416 )
2021	2021	CLEVELAND STATE UNIVERSITY	2121 EUCLID AVE	CLEVELAND	OH	44115	CUYAHOGA	USA	Cancer Detection and Diagnosis Research	000	1	7/29/2021	NEW	$412,416
														Subtotal = $412,416

Grand Total All Awards = $411,773

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Androgen signaling and sterol metabolism in metastatic prostate cancer: Functional and therapeutic implication

Award Number: R15CA252997

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2025

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