Novel Targeting of Liver Cancer Deficient of DNA Repair

缺乏 DNA 修复的肝癌的新靶向

• 批准号: 9808811
• 负责人: CHUNYING DU
• 金额: $ 20.95万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-02 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9808811
• 关键词: Address; Aflatoxins; Antineoplastic Agents; BRCA1 gene; Back; Cancer Etiology; Cell Cycle; Cell Death; Cells; Cessation of life; Chromatin; Chromatin Structure; Clinical; Combined Modality Therapy; Complement; DNA Damage; DNA Repair; DNA Single Strand Break; Death Rate; Dependence; Development; Diethylnitrosamine; Female; Food; Genome Stability; Genomic Instability; Goals; Hepatic; Hepatitis Viruses; Hepatocyte; Human; Impairment; Incidence; Inflammation; Knock-out; Ligase; Liver; Liver Cirrhosis; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of ovary; Measurement; Modeling; Monitor; Mus; Mutagens; Mutate; Mutation; National Cancer Institute; Natural regeneration; Outcome Study; Pathogenesis; Pathogenicity; Patient Care; Patient-Focused Outcomes; Patients; Pharmacology; Poly(ADP-ribose) Polymerases; Primary carcinoma of the liver cells; Prognostic Factor; Prognostic Marker; Protein Deficiency; Protein S Deficiency; Proteins; Public Health; Radiation; Regulation; Relaxation; Research; Resistance; Risk Factors; Saline; Sampling; Site; Somatic Mutation; Specimen; Testing; The Cancer Genome Atlas; Tissues; Treatment Efficacy; Treatment outcome; Ubiquitin; arm; base; cancer cell; chronic liver disease; chronic liver injury; clinically relevant; clinically significant; effective therapy; efficacy testing; experimental study; gamma-Glutamyl Hydrolase; hepatocellular carcinoma cell line; homologous recombination; inhibitor/antagonist; innovation; knock-down; liver function; male; malignant breast neoplasm; mouse model; mutational status; next generation sequencing; novel; outcome forecast; oxidative DNA damage; power analysis; pre-clinical; prognostic tool; prognostic value; programs; recombinational repair; recruit; response; screening; tumor

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.

项目概述：肝癌的死亡率肝细胞癌（HCC）的死亡率显著增加 并且是癌症死亡的主要原因之一。阐明其发病机制， 发展新的预后和有效的治疗。完整的DNA修复程序对于 抑制HCC。许多HCC危险因素包括肝遗传毒素DEN（二乙基亚硝胺），黄曲霉毒素， 食物和肝炎病毒引起严重的DNA损伤，包括DNA单链断裂（SSB）和双链断裂。 链断裂（DSB）和氧化性DNA损伤。如果DNA修复程序被破坏，受损的DNA可以 导致基因组不稳定和炎症，并加速“细胞死亡， 肝细胞的“再生”导致慢性肝病和向HCC的恶性转化。PARP PARP抑制剂是聚ADP核糖聚合酶（PARP）的药理学抑制剂， 细胞通过靶向同源重组（HR）缺陷（HRD）。我们小组最近发现布鲁斯 BRUCE KO是一种新的小鼠肝癌抑制因子，布鲁斯KO肝脏具有HRD。我们还发现了一组独特的肝癌患者 具有“有害的布鲁斯丧失”或破坏布鲁斯HR功能的体细胞突变。综合这些 观察结果表明，布鲁斯表达缺失可能是BRUCE阴性HCC的预后标志物 患者，他们也可能有HRD和敏感性PARPis和辐射。本报告的总体目标 建议是确定布鲁斯缺陷型HCC中HRD和PARP敏感性的机制，并开发 布鲁斯阴性HCC患者的新预后和治疗。根据我们的发现，我们假设 PARPis和IR敏感性取决于HCC细胞中的布鲁斯缺陷和HRD。我们进一步假设， 在BRUCE阴性的HCC患者中，肝布鲁斯丢失与预后不良相关， 阴性HCC可被PARPI和基于HRD的放射靶向。在目标1中，我们将研究PARP1是否 通过在人HCC中的互补和拯救实验，敏感性取决于布鲁斯缺陷和HRD 细胞系此外，我们将确定是否潜在的机制，人力资源功能的布鲁斯在 肝脏处于染色质松弛阶段。在目标2中，我们将确定布鲁斯阴性的预后价值， HCC患者，并与BRCAness状态共同分析。为了获得临床意义，我们将开发PARPis 和放射组合疗法在HCC PDX模型中用于布鲁斯阴性HCC，WT HCC作为对照。我们 将进一步确定PARPis敏感性的潜在机制是否与HRD和布鲁斯相关 通过使用HR标志物比较布鲁斯有效和缺陷型HCC PDX的HR修复能力来分析其缺陷。 当完成时，拟议的研究预计将通过纳入 肝布鲁斯丢失作为预测患者结局和推进PARPis治疗的新指标 治疗，这是不适用于肝癌。