Novel Targeting of Liver Cancer Deficient of DNA Repair

项目简介：肝癌死亡率大幅上升 也是导致癌症死亡的主要原因之一。迫切需要阐明其潜在的致病机制和发病机制。 发展新的预后和有效的治疗方法。一个完整的DNA修复计划对于 抑制肝细胞癌。许多肝癌危险因素包括肝脏基因毒素DEN(二乙基亚硝胺)、黄曲霉毒素和 食品和肝炎病毒会造成严重的DNA损伤，包括DNA单链断裂(SSB)和双链断裂 链断裂(DSB)和氧化DNA损伤。如果DNA修复程序被破坏，受损的DNA可能 加剧基因组的不稳定和炎症，加速细胞死亡和炎症的恶性循环 肝细胞“再生”，导致慢性肝病和癌变为肝细胞癌。PARP 抑制物(PARPis)是聚腺苷二磷酸核糖聚合酶(PARP)的药理抑制物，可消除癌症 通过靶向同源重组(HR)缺陷(HRD)的细胞。我们小组最近发现布鲁斯 是一种新的小鼠肝癌抑制因子，Bruce KO肝脏具有HRD。我们还发现了一组独特的肝细胞癌患者 患有“有害的布鲁斯缺失”或使布鲁斯HR功能失活的体细胞突变。把这些放在一起 观察表明，Bruce表达缺失可能是Bruce阴性肝细胞癌的一个预后标志 患者也可能有HRD，对PARPis和辐射敏感。这样做的总体目标是 建议确定Bruce缺陷型肝细胞癌HRD和PARPis敏感性的机制并开发 Bruce阴性肝细胞癌的新预后和新治疗。根据我们的发现，我们假设 肝癌细胞对PARPis和IR的敏感性依赖于Bruce缺陷和HRD。我们进一步假设 在Bruce阴性的肝细胞癌患者中，肝Bruce缺失与预后较差相关，而Bruce- 阴性肝细胞癌可通过PARPis和基于HRD的放射治疗进行靶向治疗。在目标1中，我们将调查PARP是否 人肝细胞癌的敏感性依赖于Bruce缺乏症和HRD的互补和挽救实验 细胞系。此外，我们将确定布鲁斯人力资源职能的潜在机制是否 肝脏处于染色质松弛阶段。在目标2中，我们将确定Bruce负性在 并与BRCAness状态进行联合分析。为了获得临床意义，我们将开发PARPis 在Bruce阴性肝癌PDX模型中进行放射联合治疗，并以WT肝癌为对照。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HR标记物比较Bruce熟练和缺乏肝细胞癌PDX的HR修复能力。 这项拟议的研究完成后，预计将通过纳入 肝Bruce损失率作为PARPis预测患者预后和推进治疗的新指标 治疗，这是不适用于肝细胞癌。

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.