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Novel Targeting of Liver Cancer Deficient of DNA Repair

Award Number: R21CA241025
ORGANIZATION: NATIONAL CANCER INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/02/2019
PERIOD OF PERFORMANCE END DATE: 08/31/2023

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Novel Targeting of Liver Cancer Deficient of DNA Repair - Project Summary: The death rate of the liver cancer hepatocellular carcinoma (HCC) has significantly increased and is one leading cause of cancer death. It is urgent to elucidating the underlying pathogenic mechanism and development of novel prognosis and effective treatment. An intact DNA repair program is essential for suppression of HCC. Many HCC risk factors including hepatic genotoxin DEN (diethylnitrosamine), aflatoxin in food, and hepatitis viruses cause severe DNA damage including DNA single strand breaks (SSBs) and double strand breaks (DSBs) and oxidative DNA damage. If the DNA repair program is disrupted, damaged DNA can contribute to genomic instability and inflammation and accelerate the vicious cycles of “cell death and regeneration” of hepatocytes, leading to chronic liver diseases and malignant transformation to HCC. PARP inhibitors (PARPis) are pharmacological inhibitors of poly ADP ribose polymerase (PARP) that eliminate cancer cells by targeting homologous recombination (HR)-deficient (HRD). Our group recently discovered that BRUCE is a new HCC suppressor in mice and BRUCE KO liver has HRD. We also found a unique group of HCC patients with “deleterious BRUCE loss” or somatic mutations that inactivate BRUCE HR function. Together these observations indicate that loss of BRUCE expression could be a prognostic marker for BRUCE-negative HCC patients and they also likely have HRD and sensitivity to PARPis and radiation. The overall objective of this proposal is to determine the mechanism for HRD and PARPis sensitivity in BRUCE deficient HCC and develop new prognosis and therapy for BRUCE negative HCC patients. Based on our findings, we hypothesize that PARPis and IR sensitivity depends on BRUCE deficiency and HRD in HCC cells. We further hypothesize that loss of hepatic BRUCE correlates with poorer prognosis in BRUCE-negative HCC patients and that BRUCE- negative HCC is targetable by PARPis and radiation based on HRD. In Aim 1, we will investigate whether PARPis sensitivity depends on BRUCE deficiency and HRD by complementation and rescue experiments in human HCC cell lines. Further, we will determine whether the underlying mechanism for the HR function of BRUCE in the liver is at the chromatin relaxation step. In Aim 2, we will determine the prognostic value of BRUCE negativity in HCC patients and co-analyzed with the BRCAness status. To gain clinical significance, we will develop PARPis and radiation combination therapy in HCC PDX models for BRUCE negative HCC with WT HCC as control. We will further determine whether the underlying mechanism for PARPis sensitivity correlates with HRD and BRUCE deficiency by comparing BRUCE proficient and deficient HCC PDX for their HR repair capacity using HR markers. When completed, the proposed study is expected to advance the management of HCC patients by incorporating hepatic BRUCE loss as a new measurement to predict patient outcome and advance their treatment by PARPis therapy, which is not available for HCC.


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 = -$898 )
2024	2020	CINCINNATI UNIV OF	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	000	2	2/5/2024	NON-COMPETING CONTINUATION	-$898
														Subtotal = -$898

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	000	2	10/12/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $174,544 )
2020	2020	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	000	2	8/13/2020	NON-COMPETING CONTINUATION	$174,544
														Subtotal = $174,544

Issue Date FY: 2019 ( Subtotal = $209,453 )
2019	2019	UNIVERSITY OF CINCINNATI	2600 CLIFTON AVE	CINCINNATI	OH	45220	HAMILTON	USA	Cancer Treatment Research	000	1	9/2/2019	NEW	$209,453
														Subtotal = $209,453

Grand Total All Awards = $383,099

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Novel Targeting of Liver Cancer Deficient of DNA Repair

Award Number: R21CA241025

ORGANIZATION: NATIONAL CANCER INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/02/2019

PERIOD OF PERFORMANCE END DATE: 08/31/2023

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