# Novel Targeting of Liver Cancer Deficient of DNA Repair

> **NIH NIH R21** · UNIVERSITY OF CINCINNATI · 2020 · $174,544

## Abstract

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 a...

## Key facts

- **NIH application ID:** 10006562
- **Project number:** 5R21CA241025-02
- **Recipient organization:** UNIVERSITY OF CINCINNATI
- **Principal Investigator:** CHUNYING DU
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $174,544
- **Award type:** 5
- **Project period:** 2019-09-02 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10006562

## Citation

> US National Institutes of Health, RePORTER application 10006562, Novel Targeting of Liver Cancer Deficient of DNA Repair (5R21CA241025-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10006562. Licensed CC0.

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