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Targeting p53 conformational defects to arrest carcinogenesis

Award Number: R01CA240718
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/01/2019
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Targeting p53 conformational defects to arrest carcinogenesis - PROJECT SUMMARY p53 mutations are believed to arise at a very early stage in carcinogenesis (Leitao et al, 2004) and were reported in tubal intraepithelial carcinoma (TIC) which is a common early precursor lesion for high-grade serous carcinoma of the ovaries (Kindelberger et al, 2007). TIC and ovarian serous carcinoma from the same patient most frequently share the same p53 mutation (Kindelberger et al, 2007). Moveover, p53 mutations are also identified in pre-neoplastic subpopulations of cells in the benign fallopian tube mucosa, termed “p53 signature” (Lee et al, 2007). Both p53 signatures and TIC lesions are found in the distal end of the fallopian tube, which is considered as a possible site of origin for ovarian cancer (Lee et al, 2007; Kurman et al, 2010). p53 mutants have the capability to promote its aggregation, which is a mechanism of inactivating the protein. Here we will determine whether aggregation of newly acquired p53 mutations in pre-neoplastic and early lesions is a defined molecular event that favors cancer progression through p53 inactivation. Our first aim is to whether aggregation of mutant p53 is present in clinical samples of p53 signatures or TICs in archival ovarian cancer specimens. Results of this aim will determine whether p53 aggregation is a feature that can be used to discriminate pre-malignant tissue from normal tissue, and can be targeted for early therapy and prevention of ovarian cancer. We previously demonstrated that p53 aggregation is an actionable event, and developed a peptide drug, ReACp53, currently in clinical development as an anti-cancer therapy. Next, we will test the hypothesis that ReACp53 can be efficacious on preventing conversion of pre-malignant lesions to full blown ovarian cancer. ReACp53 is a cell-penetrating peptide that was rationally designed to arrest p53 aggregation and results in rescue of p53 function and induction of cell death in cancers bearing aggregated mutant p53. Here we will test whether early administration of ReACp53 can prevent progression of pre-malignant lesions to ovarian cancer. Lastly we will attempt to identify a gene expression signature for ovarian tumors that carry p53 aggregates and respond to ReACp53. This will enable the rapid identification of cases for which ReACp53 will be effective and will allow us to fully estimate the fraction of tumors that are likely to respond to this 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 = -$90,104 )
2026	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	11/21/2025	NON-COMPETING CONTINUATION	-$90,104
														Subtotal = -$90,104

Issue Date FY: 2023 ( Subtotal = $349,713 )
2023	2023	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	5	6/30/2023	NON-COMPETING CONTINUATION	$349,713
														Subtotal = $349,713

Issue Date FY: 2022 ( Subtotal = $446,954 )
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	4	7/11/2022	NON-COMPETING CONTINUATION	$356,850
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	002	4	8/15/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2022	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	4	7/13/2022	SUPPLEMENT FOR EXPANSION	$90,104
														Subtotal = $446,954

Issue Date FY: 2021 ( Subtotal = $439,965 )
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	001	3	9/17/2021	SUPPLEMENT FOR EXPANSION	$83,115
2021	2021	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90024	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	3	6/14/2021	NON-COMPETING CONTINUATION	$356,850
														Subtotal = $439,965

Issue Date FY: 2020 ( Subtotal = $356,850 )
2020	2020	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	2	6/18/2020	NON-COMPETING CONTINUATION	$356,850
														Subtotal = $356,850

Issue Date FY: 2019 ( Subtotal = $356,850 )
2019	2019	UNIVERSITY OF CALIFORNIA, LOS ANGELES	10889 WILSHIRE BLVD STE 700	LOS ANGELES	CA	90095	LOS ANGELES	USA	Cancer Cause and Prevention Research	000	1	6/26/2019	NEW	$356,850
														Subtotal = $356,850

Grand Total All Awards = $1,860,228

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Targeting p53 conformational defects to arrest carcinogenesis

Award Number: R01CA240718

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 07/01/2019

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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