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Functional Analysis of p53 Polymorphic Variants

Award Number: R01CA102184
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2005
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Functional Analysis of p53 Polymorphic Variants - Project Summary This revised renewal application requests funding for years 15-19 for a proposal that is devoted to understanding the impact of genetic hypomorphs of the p53 tumor suppressor on cancer risk and therapy. The central premise is that the analysis of cancer-associated genetic hypomorphs of the p53 tumor suppressor can lend critical insight into the key functions of this tumor suppressor in cancer. The proposed research focuses on the African-specific Pro47Ser p53 hypomorph (hereafter S47) that exists in over 800,000 African-descent individuals in the United States and confers increased cancer risk in these individuals. The S47 variant of p53 is defective in the transactivation of a small subset of p53-target genes, particularly those that confer sensitivity to ferroptosis. The overarching hypothesis of the proposed research is that by understanding the biology of P47S and other cancer-associated hypomorphs, two important outcomes are met: the first is the identification of key tumor suppressor functions of p53, which are still not known. The second is that we can use mouse models in order to better understand cancer risk, and uncover superior cancer therapies, for the individuals who possess these variants. In Aim 1 we will investigate our finding that the tumor micro-environment in S47 mice is more immuno- suppressive, due to increased accumulation of myeloid-derived suppressor cells (MDSCs). MDSCs are potent immunosuppressive cells that directly limit the efficacy of immune checkpoint inhibitors. We will test the efficacy of immune checkpoint inhibitors in WT and S47 mice, and we will test combination therapy in which we target MDSCs. In Aim 2 we present data that P47S, like two other cancer-associated p53 hypomorphs Y107H and G334R, has impaired ability to transactivate the chromatin modifier PADI4, along with increased propensity to misfold and adopt a mutant p53 conformation. We will investigate the relevance of both activities to tumor suppression by p53. In Aim 3 we provide PheWAS data indicating that the S47 allele is a highly significant risk factor for bladder cancer in African Americans (p< 6x10-6, OR 7.5). In this aim we investigate the function of S47 in mouse models of bladder cancer, with the goal of better understanding the reasons underlying this significant association. We then follow our published successful protocols to identity novel chemotherapeutic drugs that show improved efficacy in S47 bladder cancer, compared to WT. The combined studies build upon a wealth of published and preliminary data, along with novel mouse models for p53 hypomorphs and the integration of human data throughout. These studies are paramount for our long term goal of understanding the genetic basis of minority cancer disparities, and improving personalized medicine approaches for individuals of African descent.


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 = $477,619 )
2025	2025	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	19	12/6/2024	SUPPLEMENT FOR EXPANSION	$86,392
2025	2025	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	19	11/21/2024	NON-COMPETING CONTINUATION	$352,104
2025	2025	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	002	19	6/2/2025	NON-COMPETING CONTINUATION	$39,123
														Subtotal = $477,619

Issue Date FY: 2024 ( Subtotal = $462,079 )
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	18	11/13/2023	NON-COMPETING CONTINUATION	$352,104
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	002	18	4/16/2024	NON-COMPETING CONTINUATION	$19,562
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	003	18	4/16/2024	SUPPLEMENT FOR EXPANSION	$4,758
2024	2024	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	18	12/5/2023	SUPPLEMENT FOR EXPANSION	$85,655
														Subtotal = $462,079

Issue Date FY: 2023 ( Subtotal = $434,908 )
2023	2023	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	002	17	9/8/2023	SUPPLEMENT FOR EXPANSION	$43,681
2023	2023	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	17	11/21/2022	NON-COMPETING CONTINUATION	$352,104
2023	2023	THE WISTAR INSTITUTE OF ANATOMY AND BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	17	3/15/2023	NON-COMPETING CONTINUATION	$39,123
														Subtotal = $434,908

Issue Date FY: 2022 ( Subtotal = $383,402 )
2022	2022	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	16	11/29/2021	NON-COMPETING CONTINUATION	$352,104
2022	2022	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	16	5/19/2022	NON-COMPETING CONTINUATION	$31,298
														Subtotal = $383,402

Issue Date FY: 2021 ( Subtotal = $391,227 )
2021	2021	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	002	15	4/1/2021	COMPETING CONTINUATION	$60,814
2021	2021	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	15	12/9/2020	COMPETING CONTINUATION	$391,227
2021	2020	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	14	4/1/2021	NON-COMPETING CONTINUATION	-$60,814
														Subtotal = $391,227

Issue Date FY: 2020 ( Subtotal = $384,750 )
2020	2020	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	14	11/14/2019	NON-COMPETING CONTINUATION	$346,275
2020	2020	WISTAR INSTITUTE OF ANATOMY AND BIOLOGY, THE	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	14	1/14/2020	NON-COMPETING CONTINUATION	$38,475
														Subtotal = $384,750

Issue Date FY: 2019 ( Subtotal = $373,207 )
2019	2019	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	13	11/22/2018	NON-COMPETING CONTINUATION	$373,207
														Subtotal = $373,207

Issue Date FY: 2018 ( Subtotal = $384,750 )
2018	2018	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	12	5/23/2018	NON-COMPETING CONTINUATION	$38,475
2018	2018	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	12	11/20/2017	NON-COMPETING CONTINUATION	$346,275
														Subtotal = $384,750

Issue Date FY: 2017 ( Subtotal = $384,750 )
2017	2017	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	11	6/7/2017	NON-COMPETING CONTINUATION	$38,475
2017	2017	WISTAR INSTITUTE OF ANATOMY & BIOLOGY	3601 SPRUCE ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	11	11/17/2016	NON-COMPETING CONTINUATION	$346,275
														Subtotal = $384,750

Issue Date FY: 2016 ( Subtotal = $384,750 )
2016	2016	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	10	12/11/2015	COMPETING CONTINUATION	$384,750
														Subtotal = $384,750

Issue Date FY: 2014 ( Subtotal = $335,745 )
2014	2014	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	9	12/16/2013	NON-COMPETING CONTINUATION	$311,516
2014	2014	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	9	5/8/2014	NON-COMPETING CONTINUATION	$24,229
														Subtotal = $335,745

Issue Date FY: 2013 ( Subtotal = $302,498 )
2013	2013	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	000	8	11/28/2012	NON-COMPETING CONTINUATION	$164,646
2013	2013	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	8	6/5/2013	NON-COMPETING CONTINUATION	$137,852
														Subtotal = $302,498

Issue Date FY: 2012 ( Subtotal = $316,755 )
2012	2012	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	002	7	4/24/2012	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$22,920
2012	2012	WISTAR INSTITUTE	36TH AT SPRUCE	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Cancer Biology Research	001	7	12/30/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$293,835
2012	2011	FOX CHASE CANCER CENTER	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	6	12/30/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $316,755

Issue Date FY: 2011 ( Subtotal = $326,484 )
2011	2011	FOX CHASE CANCER CENTER	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	000	6	12/2/2010	NON-COMPETING CONTINUATION	$302,923
2011	2011	FOX CHASE CANCER CENTER	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	001	6	5/13/2011	NON-COMPETING CONTINUATION	$23,561
														Subtotal = $326,484

Issue Date FY: 2010 ( Subtotal = $336,581 ) (Continued on the next page)
2010	2010	FOX CHASE CANCER CENTER	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	003	5	1/6/2010	COMPETING CONTINUATION	$336,581
2010	2010	FOX CHASE CANCER CENTER	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	002	5	1/5/2010	COMPETING CONTINUATION	-$336,581
2010	2010	FOX CHASE CANCER CENTER	7701 BURHOLME AVENUE	PHILADELPHIA	PA	19111	PHILADELPHIA	USA	Cancer Biology Research	001	5	1/1/2010	COMPETING CONTINUATION	$336,581
Grand Total All Awards = $6,937,334

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Functional Analysis of p53 Polymorphic Variants

Award Number: R01CA102184

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2005

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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