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NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer

Award Number: R01CA234162
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/22/2019
PERIOD OF PERFORMANCE END DATE: 04/30/2026

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NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer - Androgen deprivation therapy (ADT) is effective in treating metastatic prostate adenocarcinoma (PADC), but all patients inevitably relapse with castrate resistant prostate cancer (CRPC). Most CRPCs remain dependent on androgen receptor (AR) signaling, but a significant fraction lack AR expression, become AR signaling independent, and aberrantly express neuroendocrine lineage markers (NEPC). The incidence of NEPC variants among CRPC has increased as more patients benefit from improved ADTs like enzalutamide and abiraterone acetate. This suggests increasingly stringent AR signaling blockade is driving development of NEPC. This is an important clinical problem because NEPC is aggressive and lethal; development of effective therapies is hampered by limited understanding of relevant molecular mechanisms. NEPC clearly arises from ARpos CRPC as they share clonal origin in patients that harbor both. We have determined that genetic inactivation of the RB1/TRP53 tumor suppressor genes cooperate to facilitate transformation of ARpos PADC to NEPC through derepression of epigenetic reprogramming factors. Inhibiting these reprogramming factors reverses NEPC transformation and restores ADT sensitivity, demonstrating that epigenetic changes are involved. We hypothesize that a change in NOTCH-ASCL1 signaling triggers the epigenetic reprogramming underlying NEPC transformation. This hypothesis has clinical ramifications as the pathway could conceivably be manipulated therapeutically to delay or reverse NEPC transformation, extending the duration of beneficial ADT clinical responses in some patients. We propose three specific aims using novel prostate cancer mouse models and unique human clinical specimens to test this hypothesis, characterize how PADC cells transform into NEPC cells, and explore novel therapeutic approaches for the treatment of this lethal form of prostate cancer. We will: 1) Test if NOTCH signaling is sufficient to maintain an androgen dependent PADC phenotype; 2) Characterize how prostate cancer cells transition from PADC to NEPC; 3) Determine whether epigenetic modulating drugs reverse NEPC transformation and ADT resistance via NOTCH-ASCL1 signaling. The long term goal of this project is to improve prostate cancer therapy by advancing mechanistic understanding of lineage plasticity as a mechanism of acquired therapeutic 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: 2024 ( Subtotal = $382,429 )
2024	2024	HEALTH RESEARCH, INC.	665 ELM ST	BUFFALO	NY	14203	ERIE	USA	Cancer Cause and Prevention Research	000	6	4/12/2024	NON-COMPETING CONTINUATION	$382,429
														Subtotal = $382,429

Issue Date FY: 2023 ( Subtotal = $637,095 )
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Cause and Prevention Research	000	5	4/24/2023	NON-COMPETING CONTINUATION	$629,075
2023	2023	HEALTH RESEARCH, INC.	ELM & CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Cause and Prevention Research	001	5	4/25/2023	SUPPLEMENT FOR EXPANSION	$8,020
														Subtotal = $637,095

Issue Date FY: 2022 ( Subtotal = $164,887 )
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Cause and Prevention Research	001	4	6/10/2022	SUPPLEMENT FOR EXPANSION	$55,630
2022	2022	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Cause and Prevention Research	000	4	6/8/2022	NON-COMPETING CONTINUATION	$109,257
														Subtotal = $164,887

Issue Date FY: 2021 ( Subtotal = $626,214 )
2021	2021	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Cause and Prevention Research	000	3	4/26/2021	NON-COMPETING CONTINUATION	$577,631
2021	2021	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Cause and Prevention Research	001	3	9/20/2021	SUPPLEMENT FOR EXPANSION	$48,583
														Subtotal = $626,214

Issue Date FY: 2020 ( Subtotal = $577,631 )
2020	2020	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Cause and Prevention Research	000	2	4/22/2020	NON-COMPETING CONTINUATION	$577,631
														Subtotal = $577,631

Issue Date FY: 2019 ( Subtotal = $614,981 )
2019	2019	HEALTH RESEARCH, INC.	ELM AND CARLTON ST	BUFFALO	NY	14263	ERIE	USA	Cancer Cause and Prevention Research	000	1	5/22/2019	NEW	$614,981
														Subtotal = $614,981

Grand Total All Awards = $3,003,237

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NOTCH signaling controls transformation to androgen independent neuroendocrine prostate cancer

Award Number: R01CA234162

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/22/2019

PERIOD OF PERFORMANCE END DATE: 04/30/2026

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