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Re-engineered Mitochondrially Targeted p53 Gene Therapy in Liver Cancer

Award Number: R21CA241015
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2021
PERIOD OF PERFORMANCE END DATE: 12/31/2023

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Re-engineered Mitochondrially Targeted p53 Gene Therapy in Liver Cancer - Abstract: Hepatocellular carcinoma (HCC), the most common cancer of the liver, is the third leading cause of cancer death worldwide. In the U.S., the overall 5-year survival rate for HCC is only 17% and only 3% for distantly metastasized HCC. Surgical resection and liver transplantation are the current standard of care for HCC, but only ~5% qualify for resection due to cirrhosis. Limited organ availability also severely restricts the number of transplants. New targeted agents for HCC including kinase inhibitors and immunotherapies show promise, but patients using targeted agents will inevitably develop drug resistance. Effective new therapies for HCC are urgently needed. We propose a new, re-engineered p53 tumor suppressor-apoptotic protein hybrid for gene therapy of HCC called p53-Bad*. Wild-type p53 was approved for gene therapy as Gendicine® for cancers in China with limited success. Limited efficacy may be related to the dominant negative effect that mutant p53 exerts over wt p53. As nuclear p53 activity is dependent on homo-tetramerization, mutant p53 in cancer cells can also tetramerize with wt p53 to cause its inactivation. Mutant p53 can also have gain-of-function and other activities that can counter the effects of wt p53. To overcome this limitation, a potent p53 fusion protein with novel mechanisms of action is proposed here that overcomes dominant negative inhibition and causes apoptosis regardless of the p53 status of cancer cells. By fusing p53 to an apoptotic BH3 protein with an inherent mitochondrial targeting signal, such as Bad, this increases apoptosis further by combining the apoptotic effects of mitochondrial p53 with those of pro-apoptotic BH3 proteins. p53-Bad* (a mutant version of Bad with increased mitochondrial localization) is our top cancer cell-killing construct. We hypothesize that the combination of p53 and BH3 proteins at the mitochondria, with liver cancer specificity driven by a modified alpha fetoprotein (AFP) promoter, will potently induce apoptosis in liver cancer both in vitro (regardless of p53 status), and in vivo in zebrafish and mouse models. Zebrafish are an ideal model system for studying human cancer, with “histologic and genetic similarities between zebrafish and human tumors” while an orthotopic xenograft mouse model is an important step toward translation. The following aims are proposed: Aim 1: a. p53-BH3 fusion (p53-Bad*) will localize to the mitochondria and cause potent apoptosis in relevant hepatocellular carcinoma (HCC) cell lines regardless of cellular p53 status; b. the use of modified/combination AFP promoters will confer liver cancer cell specificity and kill HCC cells and not normal human cells. Aim 2: Expression of p53-Bad* under the liver specific promoter fabp10a in zebrafish, crossed with a liver cancer zebrafish model will produce offspring with reduced expression of liver cancer specific phenotypes. Aim 3: p53-Bad* (expressed in adenovirus with the optimized HCC specific promoter) will shrink liver tumors in an orthotopic xenograft mouse model of HCC (using AFP- expressing human HCC liver cells, Hep3B). The ultimate goal of this study is the development of a new, effective therapy for treatment of HCC patients worldwide.


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 = -$683 )
2024	2022	UNIVERSITY OF UTAH	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Treatment Research	000	2	5/13/2024	NON-COMPETING CONTINUATION	-$683
														Subtotal = -$683

Issue Date FY: 2022 ( Subtotal = $209,604 )
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Treatment Research	001	2	5/20/2022	NON-COMPETING CONTINUATION	$17,112
2022	2022	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Treatment Research	000	2	12/31/2021	NON-COMPETING CONTINUATION	$192,492
														Subtotal = $209,604

Issue Date FY: 2021 ( Subtotal = $178,234 )
2021	2021	UNIVERSITY OF UTAH, THE	201 PRESIDENTS CIR	SALT LAKE CITY	UT	84112	SALT LAKE	USA	Cancer Treatment Research	000	1	12/10/2020	NEW	$178,234
														Subtotal = $178,234

Grand Total All Awards = $387,155

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Re-engineered Mitochondrially Targeted p53 Gene Therapy in Liver Cancer

Award Number: R21CA241015

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2021

PERIOD OF PERFORMANCE END DATE: 12/31/2023

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