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The regulation of mutant p53 protein accumulation in cancer: molecular basis and therapeutic potential

Award Number: R01CA229257
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2021
PERIOD OF PERFORMANCE END DATE: 06/30/2026

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The regulation of mutant p53 protein accumulation in cancer: molecular basis and therapeutic potential - Abstract Tumor suppressor p53 is the most frequently mutated gene in human cancer, including colorectal cancer (CRC). Many tumor-associated mutant p53 (mutp53) proteins not only lose the tumor suppressive function of wild-type p53, but also gain new oncogenic activities to promote tumorigenesis, which is defined as the “gain-of-function” (GOF). Mutp53 proteins often become stable and accumulate to very high levels in cancer, which is critical for mutp53 GOF in tumorigenesis. Destabilizing mutp53 protein is being actively tested as a novel and promising strategy for cancer therapy. However, the mechanism of mutp53 accumulation in cancer is poorly understood, which hinders the development of effective strategies for cancer therapy. MDM2 is the most critical negative regulator of p53. MDM2 isoform B (MDM2B), a spliced isoform of MDM2, is frequently overexpressed in human cancer, and plays an important role in tumorigenesis. Currently, the mechanisms underlying MDM2B-mediated mutp53 accumulation and MDM2B overexpression in cancer are poorly understood. Identifying their underlying mechanisms has the direct potential to develop effective strategies to treat cancers carrying mutp53. The goal of this study is to determine the mechanism of mutp53 accumulation in CRC to provide novel therapeutic targets/strategies for CRC carrying mutp53. Based on our preliminary studies, we hypothesize that MDM2B overexpression is a critical mechanism underlying mutp53 protein accumulation and GOF in CRC, and furthermore, MDM2B and its signaling pathway can be targeted for therapy in CRC carrying mutp53. We will test our hypothesis by following specific aims: 1) determine whether MDM2B overexpression is a critical mechanism underlying mutp53 accumulation and GOF in CRC using different mouse colorectal tumor models, and identify mechanisms underlying MDM2B-mediated mutp53 accumulation; and 2) identify mechanisms underlying MDM2B overexpression in CRC, and test whether targeting MDM2B and its signaling pathway can inhibit mutp53 accumulation and GOF in CRC. We anticipate that this proposed study will provide new paradigms regarding mutp53 accumulation, tumor-promoting function of MDM2B, and MDM2B overexpression in CRC. If accomplished successfully, results from this study will have potential to develop MDM2B and its signaling pathway as novel therapeutic targets for CRC carrying mutp53.


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 = $418,341 )
2025	2025	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	000	5	6/30/2025	NON-COMPETING CONTINUATION	$418,341
														Subtotal = $418,341

Issue Date FY: 2024 ( Subtotal = $397,425 )
2024	2024	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	002	4	6/5/2024	NON-COMPETING CONTINUATION	$397,425
2024	2023	RUTGERS THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	001	3	3/21/2024	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$40,298
2024	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08901	MIDDLESEX	USA	Cancer Biology Research	000	2	3/21/2024	NON-COMPETING CONTINUATION	-$40,298
														Subtotal = $397,425

Issue Date FY: 2023 ( Subtotal = $409,975 )
2023	2023	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	65 BERGEN ST	NEWARK	NJ	07107	ESSEX	USA	Cancer Biology Research	001	3	6/1/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$409,975
2023	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	2	6/1/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $409,975

Issue Date FY: 2022 ( Subtotal = $409,975 )
2022	2022	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	2	5/16/2022	NON-COMPETING CONTINUATION	$409,975
														Subtotal = $409,975

Issue Date FY: 2021 ( Subtotal = $413,128 )
2021	2021	RUTGERS, THE STATE UNIVERSITY OF NEW JERSEY	195 LITTLE ALBANY ST	NEW BRUNSWICK	NJ	08903	MIDDLESEX	USA	Cancer Biology Research	000	1	5/17/2021	NEW	$413,128
														Subtotal = $413,128

Grand Total All Awards = $2,048,844

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The regulation of mutant p53 protein accumulation in cancer: molecular basis and therapeutic potential

Award Number: R01CA229257

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2021

PERIOD OF PERFORMANCE END DATE: 06/30/2026

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