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Targeting FOXA2/AP-1 axis to overcome lineage plasticity and therapy resistance in castration-resistant prostate cancer

Award Number: R01CA299202
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/21/2025
PERIOD OF PERFORMANCE END DATE: 01/31/2030

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Targeting FOXA2/AP-1 axis to overcome lineage plasticity and therapy resistance in castration-resistant prostate cancer - PROJECT SUMMARY Background: Prostate cancer (PCa) can develop resistance to androgen receptor (AR)-targeted therapies and progress to AR-indifferent stages, such as NEPC or DNPC, through lineage plasticity. While several driver transcription factors for AR-indifferent PCa have been identified, the mechanisms by which lineage-specific developmental enhancers regain accessibility to those transcription factors remain unclear. FOXA family proteins are pioneer transcription factors that modulate chromatin accessibility by maintaining an accessible nucleosome state. In AR-driven PCa, FOXA1 is overexpressed and defines AR chromatin binding. In AR-independent PCa, FOXA1 expression decreases, while FOXA2 expression significantly increases. Our preliminary studies indicate that FOXA2 binds to three different classes of lineage-specific enhancers in three major subtypes of AR- indifferent CRPC, suggesting it may function as a pan-plasticity driver. Expressing FOXA2 in luminal PCa cells suppresses FOXA1 and allows FOXA2 to occupy all subclasses of lineage-specific enhancers, potentially driving cells into a highly plastic multilineage transition state. Mechanistically, FOXA2 chromatin binding is stabilized by LSD1-mediated demethylation, and FOXA2 can cooperatively bind to chromatin with JUN and induce the transcriptional reprogramming of AP-1, facilitating the multilineage transition. Objective/Hypothesis: We hypothesize that in response to AR-targeted therapies, FOXA2, in collaboration with AP-1, acts as a pan-plasticity driver by opening multiple classes of developmental enhancers to establish an adaptive multilineage transition state, and that targeting the FOXA2-AP-1 axis can suppress lineage plasticity and thus overcome PCa resistance to AR-targeted therapies. Specific Aims: Aim 1 will determine whether FOXA2 expression drives luminal PCa cells into a multilineage transition state. We will determine FOXA2 chromatin binding to multiple classes developmental enhancers in cell lines and patient-derived AR-independent CRPC models and then will overexpress FOXA2 in luminal PCa cell lines to assess whether FOXA2 can promote an AR-independent multilineage transition. Aim 2 will investigate how FOXA2 rewires AP-1 to drive lineage reprogramming. We will examine the interaction between FOXA2 and JUN on chromatin and then alter AP-1 expression to understand the role of AP-1 reprogramming in the lineage plasticity. Aim 3 will assess the therapeutic potential of inhibitors targeting the FOXA2-AP-1 axis in CRPC PDX models. We will evaluate the efficacy of a small molecule inhibitor targeting AP-1 chromatin binding in combination with a newly designed peptide-based LSD1 inhibitor using a series AR-independent PDX models. Impact: The short-term impact of this study, if successful, is to provide mechanistic insights into the function and molecular activity of FOXA2 in driving PCa lineage plasticity and test a combination approach to target the FOXA2-AP-1 axis in preclinical CRPC models. The long-term impact is to translate this treatment strategy into clinical trials in a well-defined subset of AR-independent PCa patients to improve patient outcomes.


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 = $376,750 )
2026	2026	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Cancer Treatment Research	000	2	1/9/2026	NON-COMPETING CONTINUATION	$376,750
														Subtotal = $376,750

Issue Date FY: 2025 ( Subtotal = $415,902 )
2025	2025	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Cancer Treatment Research	000	1	2/21/2025	NEW	$415,902
2025	2025	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Cancer Treatment Research	001	1	8/27/2025	NEW	-$415,902
2025	2025	UNIVERSITY OF MASS AT BOSTON	100 WILLIAM T MORRISSEY BLVD	DORCHESTER	MA	02125	SUFFOLK	USA	Cancer Treatment Research	002	1	9/3/2025	NEW	$415,902
														Subtotal = $415,902

Grand Total All Awards = $792,652

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Targeting FOXA2/AP-1 axis to overcome lineage plasticity and therapy resistance in castration-resistant prostate cancer

Award Number: R01CA299202

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/21/2025

PERIOD OF PERFORMANCE END DATE: 01/31/2030

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