Tuesday, July 1, 2025 7/1/2025

Unravel a novel metabolic pathway orchestrating prostate cancer progression and therapeutic resistance

Award Number: R01CA256158
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/03/2022
PERIOD OF PERFORMANCE END DATE: 08/31/2027

Group Awards By:

View Award Description

Unravel a novel metabolic pathway orchestrating prostate cancer progression and therapeutic resistance - Summary Prostate cancer is the second leading cause of cancer deaths in the United States. While androgen ablation therapy (ABT) is the mainstay of therapy for men with prostate cancer, most patients with prostate cancer will inevitably develop castration-resistant prostate cancer (CRPC), which no longer responds to ABT treatment. Thus, understanding of the mechanisms leading to CRPC and ABT resistance is urgently needed. Several mechanisms account for the occurrence of CRPC, such as activation of 3-kinase/Akt signaling pathway, which plays a critical role in cell proliferation and cell survival, and higher expression of AR and AR splicing variants, which facilitate prostate cancer cell survival under very low androgen concentrations. Of note is that prostate cancer stem cells (PCSCs) also known as cancer initiating cells (CICs), which account for a small cell population prostate cancer cells, are critically involved in the development of CRPC. But how PCSCs are regulated and how they can be pharmacologically targeted are currently not well understood. While several stem cell factors such as SOX2 playing an important role in maintaining PCSC pool and functions are identified, there is no effective strategy to block the action of these proteins in order to eradicate PCSCs within the cancer. Thus, identifying key druggable targets maintaining PCSCs could provide novel paradigms and effective strategies for prostate cancer therapy and overcoming ABT resistance. Our goal in this study is to identify a novel mechanism underlying PCSC maintenance, which could be harnessed to develop an effective strategy for CRPC targeting. Using systematic metabolomics and transcriptomics in conjunction with biochemical validation and in vivo tumor development assays, we unraveled a novel oncogenic and metabolic signaling pathway, which was elevated during ABT treatment and in advanced human prostate cancer, is critical for maintaining the stemness and pool of PCSCs and CRPC development. Of note, we observed aberrant AMPK activation and AMPK-dependent mitochondria fission upon loss of this metabolic signaling, correlated with the defect in stemness and pool of PCSCs and prostate cancer progression. In light of these findings, we hypothesized that this newly discovered metabolic signaling is crucial for restricting aberrant AMPK-dependent mitochondrial fission to maintain the pool and stemness of PCSCs, thereby leading to CRPC and ABT resistance. Our hypothesis has been formulated based on our solid and innovative preliminary results. In this proposal, we proposed three specific aims to test this paradigm-shift hypothesis. Our study has not only revolutionized and significantly advanced our understanding of cancer metabolism in PCSC regulation, but also offered a promising strategy to treat advanced prostate cancer and overcoming ABT resistance.


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	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Biology Research	001	3	1/21/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$35,222
2025	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	1	1/21/2025	NEW	-$35,222
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $495,102 )
2024	2024	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Biology Research	001	4	8/13/2024	NON-COMPETING CONTINUATION	$495,102
2024	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Biology Research	000	3	10/16/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$0
														Subtotal = $495,102

Issue Date FY: 2023 ( Subtotal = $506,358 )
2023	2023	DUKE UNIVERSITY	2200 W MAIN ST	DURHAM	NC	27705	DURHAM	USA	Cancer Biology Research	002	3	9/6/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$506,358
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	001	2	9/6/2023	NON-COMPETING CONTINUATION	-$487,487
2023	2023	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	2	1/30/2023	NON-COMPETING CONTINUATION	$487,487
														Subtotal = $506,358

Issue Date FY: 2022 ( Subtotal = $497,437 )
2022	2022	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BLVD	WINSTON SALEM	NC	27157	FORSYTH	USA	Cancer Biology Research	000	1	12/30/2021	NEW	$497,437
														Subtotal = $497,437

Grand Total All Awards = $1,498,897

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Unravel a novel metabolic pathway orchestrating prostate cancer progression and therapeutic resistance

Award Number: R01CA256158

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/03/2022

PERIOD OF PERFORMANCE END DATE: 08/31/2027

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer