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Characterizing the cooperative role of E2F1 and interacting proteins in driving advanced prostate cancer

Award Number: R03CA308672
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Characterizing the cooperative role of E2F1 and interacting proteins in driving advanced prostate cancer - PROJECT SUMMARY/ABSTRACT Prostate cancer arises as an androgen driven disease, and androgen receptor (AR)-targeted therapies are the mainstay of treatment for men with advanced disease. One mechanism of resistance is ahistologic transformation from an AR-driven prostate adenocarcinoma to an AR-independent small cell neuroendocrine carcinoma, often referred to as neuroendocrine prostate cancer (NEPC). NEPC is clinically aggressive, frequently metastasizes to visceral organs, and carries a poor prognosis. A thorough molecular understanding of NEPC progression is needed for the development of strategies to treat, prevent, or reverse the development of this lethal disease. Although NEPC tumors arise clonally from prostate adenocarcinoma, there is significant epigenetic and transcriptomic dysregulation that occurs during the lineage plasticity process. Mechanistically, we still do not know how these alterations arise and how best to leverage these alterations as a therapeutic opportunity. Based on published reports and on our preliminary data, E2F1 is over-expressed in the majority of NEPC cases and in a subset of CRPC cases and is associated with a poorer prognosis compared to CRPC with low to no E2F1 expression. However, little is known about the role of E2F1 in the progression from CRPC to NEPC. Our preliminary and published data from patient tumors and in vivo, in vitro and ex vivo models (patient- derived organoids) suggest that E2F1 drives a reprogramming of chromatin accessibility which in turn, results in a NEPC-associated change in gene expression and that this is potentially mediated through a physically interaction with specific NEPC-associated co-factors and transcription factors. Our long-term goal is to develop new biomarker-driven therapeutic strategies for treating patients with advanced prostate cancer and untreatable NEPC. The objective here is to identify the key molecular events and mechanisms underlying lineage plasticity in prostate cancer. This would allow for early therapeutic intervention and improve patient outcome. Our over- arching hypothesis, which is based on our published and preliminary data, is that specific molecular alterations (e.g. RB1 loss and E2F1 induction) in prostate cancer cells drive the progression of CRPC tumors towards NEPC resulting in changes to chromatin accessibility and interactions with specific pro-stem cell- and neural lineage- associated transcription factors to drive a NEPC-associated change in gene expression. To address this hypothesis, we will define essential E2F1-transcriptional complex proteins that mediate the gene expression program driving and maintaining NEPC-progression (Aim 1) and determine if E2F1 is essential in mediating the gene expression program associated with the transition from CRPC towards NEPC (Aim 2). Successful completion of these Aims will provide unique insights into NEPC development, identify potential targetable mediators of lineage plasticity, and a timely and unique opportunity for the early detection of patients with E2F1- expressing CRPC that are evolving towards NEPC that may not respond to standard-of-care anti-AR therapy.


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 = $169,291 )
2026	2026	WEILL MEDICAL COLLEGE OF CORNELL UNIVERSITY	575 LEXINGTON AVE FL 9	NEW YORK	NY	10022	NEW YORK	USA	Cancer Cause and Prevention Research	000	1	4/9/2026	NEW	$169,291
														Subtotal = $169,291

Grand Total All Awards = $169,291

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Characterizing the cooperative role of E2F1 and interacting proteins in driving advanced prostate cancer

Award Number: R03CA308672

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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