qHTS of Patient Derived HCC Models to Identify Novel Probes/Therapeutic Agents

摘要：患者来源的肝细胞癌模型的QHTS以确定新的探针/治疗药物 肝细胞癌(HCC)占原发性肝癌的90%，在全球范围内每年都有 每年的发病率约为80万，是癌症相关死亡的第二大原因。肝癌发病率最高 在南亚，男性的发病率是男性的2.4倍，非高加索人的发病率是白人的2倍。肝细胞癌与 有一系列环境和感染性病因，包括感染嗜肝病毒(乙肝病毒和丙型肝炎病毒)， 非酒精性脂肪性肝炎(NASH)、非酒精性脂肪性肝病(NAFLD)、酒精和黄曲霉毒素暴露， 其中每一种都与肝脏的发病机制有关。80%-90%的肝细胞癌患者存在肝硬变 代表了最重要的单一风险因素。在发达国家，肝癌的发病率正在上升，原因是 代谢综合征患病率和较高的丙型肝炎病毒感染率。肥胖、胰岛素抵抗和血脂异常， 已经成为NAFLD、肝硬变和肝细胞癌的重要原因。NASH和NAFLD是全球流行病 有证据表明，患NASH相关性肝细胞癌的风险与肝炎相关的肝硬变有关。而当 在美国，只有5%-20%的NAFLD患者进展为NASH，这意味着2%-5%的总人口 都有患上肝癌的风险。由于在发病初期缺乏明显的症状，大多数肝细胞癌患者 被诊断出患有晚期疾病，并存活6个月。接受治疗的患者的中位生存期 只有6-20个月。局限期、区域性和远期肝癌的5年生存率分别为31.1%、10.7% 分别为2.8%和2.8%。肝移植、外科切除和消融术的应答率很高 治疗早期肝细胞癌的潜力。然而，只有10%-23%的肝细胞癌患者得到了足够早的诊断 接受这样的治疗。经动脉化疗栓塞术或放射栓塞术是保留的患者的选择 肝功能和性能状况。细胞毒药物联合全身化疗治疗晚期肝细胞癌 联合用药的应答率只有10%-20%，而且不能延长总体生存时间。索拉非尼，一种 分子靶向的多种酪氨酸激酶抑制剂被批准用于治疗肝癌，但通过以下方式提高总体存活率 只有3个月左右。另一种多酪氨酸激酶抑制剂(TKI)Regorafenib被批准用于患有 服用索拉非尼的肿瘤进展也只能延长3个月的生存期。尽管有少量的生存福利 在肝细胞癌的多TKI治疗中，还有几个正在临床开发中。免疫检查点免疫疗法 (pembrolizumab或nivolumab)靶向抗程序性细胞死亡-1蛋白(PD-1)之间的相互作用 受体及其配体(PD-L1或PD-L2)，或抗细胞毒性T淋巴细胞抗原-4(CTLA-4)(Tremlimumab)， 也在为肝细胞癌进行临床开发。然而，仍然存在对新的和未得到满足的紧急需求 有效的肝细胞癌疗法。肝细胞癌的病因学和遗传异质性促使药物的发现和开发 很有挑战性。我们提出了一种表型qHTS策略来识别新的探针或治疗线索 独特的患者来源的肝癌细胞系模型的乙肝病毒，丙型肝炎病毒和非酒精性肝炎的病因。

Summary: qHTS of Patient Derived HCC Models to Identify Novel Probes/Therapeutic Agents Hepatocellular Carcinoma (HCC) accounts for > 90% of primary liver cancers and has an annual worldwide incidence of ~800,000 per year, and is the 2nd leading cause of cancer related death. HCC incidence is highest in South Asia and is ~2.4-fold more prevalent in males, and ~2-fold higher in non-Caucasians. HCC is associated with a range of environmental and infective etiologies including infection with hepatotropic viruses (HBV & HCV), non-alcoholic steatohepatitis (NASH), nonalcoholic fatty liver disease (NAFLD), alcohol and aflatoxin exposure, each of which contributes to liver pathogenesis. Liver cirrhosis is present in 80-90% of HCC patients and represents the single most important risk factor. HCC incidence is rising in developed countries due to a growing prevalence of metabolic syndrome and higher HCV infection rates. Obesity, insulin resistance and dyslipidemia, have emerged as a significant cause of NAFLD, cirrhosis, and HCC. NASH and NAFLD are global epidemics and evidence suggests that the risk of developing NASH related HCC is > for hepatitis-related cirrhosis. While only 5-20% of NAFLD patients progress to NASH in the USA, this means that 2-5% of the general population are at risk of developing HCC. Due to the lack of obvious symptoms during its initial stages, most HCC patients are diagnosed with advanced disease and survive <6 months. The median survival of patients receiving therapy is only ~6-20 months. 5-year survival rates for localized, regional and distant stages of HCC are 31.1%, 10.7% and 2.8% respectively. Liver transplantation, surgical resection, and ablation offer high response rates with potential for cures for early stage HCC. However, only 10%-23% of HCC patients are diagnosed early enough for such therapies. Trans-arterial chemoembolization or radioembolization are options for patents with preserved hepatic function and performance status. Systemic chemotherapy of advanced HCC with cytotoxic agents or drug combinations elicit response rates of only 10%-20%, and don’t prolong overall survival. Sorafenib, a molecularly targeted inhibitor of multiple tyrosine kinases is approved for HCC but improves overall survival by only ~3 months. Regorafenib, another multi-tyrosine kinase inhibitor (TKI) is approved for HCC patients with tumors progressing on sorafenib, also prolongs survival for only ~3 months. Despite the modest survival benefits of multi-TKI’s for HCC, several more are in clinical development. Immune checkpoint immunotherapies (Pembrolizumab or Nivolumab) targeting interactions between the anti-programmed cell death-1 protein (PD-1) receptor and its ligands (PD-L1 or PD-L2), or anti-cytotoxic T-lymphocyte antigen-4 (CTLA-4) (Tremelimumab), are also in clinical development for HCC. However, there remains an urgent unmet need for new and effective HCC therapies. The etiologic and genetic heterogeneity of HCC makes drug discovery/development challenging. We propose a phenotypic qHTS strategy to identify novel probes or therapeutic leads using unique patient derived HCC cell line models of HBV, HCV and NASH etiologies.