Novel Targeting of Liver Cancer Deficient of DNA Repair

缺乏 DNA 修复的肝癌的新靶向

• 批准号: 10006562
• 负责人: CHUNYING DU
• 金额: $ 17.45万
• 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 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10006562
• 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 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; cell regeneration; 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.

项目摘要：肝癌肝细胞癌（HCC）的死亡率已显着提高 并且是癌症死亡的主要原因。迫切要阐明潜在的致​​病机制和 新的预后和有效治疗的发展。完整的DNA维修程序对于 抑制HCC。许多HCC危险因素，包括肝基因毒素DEN（二乙基硝基胺），黄曲霉毒素 食物和肝炎病毒会导致严重的DNA损伤，包括DNA单链断裂（SSB）和双重 链断裂（DSB）和氧化DNA损伤。如果DNA维修程序被禁用，则受损的DNA可以 有助于基因组不稳定性和注射，并加速“细胞死亡和 肝细胞的再生”，导致慢性肝病和恶性转化为HCC。 抑制剂（PARPIS）是消除癌症的聚ADP核糖聚合酶（PARP）的药物抑制剂 通过靶向同源重组（HR）缺陷（HRD）的细胞。我们的小组最近发现布鲁斯 是小鼠的新型HCC抑制剂，Bruce KO肝脏具有HRD。我们还发现了一组独特的HCC患者 带有“有害的布鲁斯损失”或使Bruce HR功能失活的躯体突变。在一起 观察结果表明，布鲁斯表达的丧失可能是布鲁斯阴性HCC的预后标记 患者和他们也可能对parpis和辐射具有HRD和敏感性。总体目标 建议是确定Bruce缺乏HCC的HRD和PARPIS敏感性的机制并发展 Bruce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Bruce缺乏和HRD。我们进一步假设 Bruce阴性HCC患者的预后较差，肝脏的丢失与Bruce- 负HCC由PARPI和基于HRD的辐射靶向。在AIM 1中，我们将调查Parpis是否 敏感性取决于Bruce缺乏症和HRD，通过完成和救援实验 细胞系。此外，我们将确定布鲁斯在 肝脏处于染色质松弛步骤。在AIM 2中，我们将确定布鲁斯谈判的预后价值 HCC患者并与BRCANESS状态共同分析。为了获得临床意义，我们将发展Parpis HCC PDX模型中的Bruce负HCC的辐射组合疗法和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Bruce相关 通过比较Bruce使用HR标记的HR修复能力的Bruce熟练且缺乏HCC PDX的缺陷。 完成后，预计拟议的研究将通过合并来推动HCC患者的管理 肝布斯损失是一种新的测量，以预测患者的结果并推进帕尔皮斯的治疗 疗法，无法用于HCC。