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.

Public Health Relevance

The proposed research is highly relevant to public health because it should elucidate a hitherto unknown DNA damage repair mechanism underlying the development of the most common form of malignancy in the liver - hepatocellular carcinoma (HCC) - by loss of the new HCC suppressor BRUCE. Furthermore, the translational fallout of this study is enormous because the mechanism-driven development of both prognostic tools and PARP inhibitor therapy will innovate the prognosis and treatment of HCC. Because PARP inhibitor therapy is not yet available for HCC treatment, the outcome of the study will advance HCC patient care - the key goal of the National Cancer Institute.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21CA241025-02
Application #
10006562
Study Section
Special Emphasis Panel (ZCA1)
Program Officer
Venkatachalam, Sundaresan
Project Start
2019-09-02
Project End
2021-08-31
Budget Start
2020-09-01
Budget End
2021-08-31
Support Year
2
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Cincinnati
Department
Anatomy/Cell Biology
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221