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

患者来源的 HCC 模型的 qHTS 来识别新型探针/治疗药物

• 批准号: 10355522
• 负责人: Paul A. Johnston
• 金额: $ 45.21万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-03-01 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10355522
• 关键词: 3-Dimensional; Ablation; Affect; Aflatoxins; Africa South of the Sahara; Alcohols; Asia; BAY 54-9085; CTLA4 gene; Cancer Etiology; Cell Cycle; Cell model; Cessation of life; Chemoembolization; China; Cirrhosis; Complex; Cytotoxic agent; Developed Countries; Development; Diagnosis; Distant; Drug Combinations; Dyslipidemias; Early Diagnosis; Epidemic; Epidemiology; Etiology; Excision; Exhibits; FRAP1 gene; General Population; Genetic Heterogeneity; Geographic Locations; Growth; Hepatic; Hepatitis; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Hepatocyte; Incidence; Infection; Insulin Resistance; KDR gene; Legal patent; Ligands; Liver; Liver Cirrhosis; Malignant Neoplasms; Malignant neoplasm of liver; Metabolic syndrome; Mitogen-Activated Protein Kinases; Modeling; Molecular Target; Mongolia; Morbidity - disease rate; Mutation; Nexavar; Nivolumab; Obesity; Operative Surgical Procedures; Organoids; PDGFRB gene; Pathogenesis; Pathway interactions; Patients; Performance Status; Performance Status 0; Phenotype; Populations at Risk; Prevalence; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Prognosis; Protein Tyrosine Kinase; Race; Radioembolization; Risk; Risk Factors; Signal Pathway; Southeastern Asia; Survival Rate; Symptoms; TP53 gene; Telomere Maintenance; Therapeutic; Therapeutic Agents; Tumor stage; Tyrosine Kinase Inhibitor; Virus; advanced disease; anti-PD-1; beta catenin; cancer type; checkpoint therapy; chemotherapy; chromatin remodeling; clinical development; drug development; drug discovery; hepatocellular carcinoma cell line; immune checkpoint; improved; infection rate; inhibitor; kinase inhibitor; liver cancer model; liver function; liver transplantation; male; mortality; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; novel; pembrolizumab; preservation; programmed cell death ligand 1; raf Kinases; receptor; response; sex; tumor

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.

总结：用于鉴定新型探针/治疗剂的患者衍生HCC模型的qHTS 肝细胞癌（HCC）占原发性肝癌的> 90%，并且每年在全世界范围内发生。 发病率约为每年800，000人，是癌症相关死亡的第二大原因。HCC发病率最高 在南亚，男性中的患病率高约2.4倍，非高加索人中高约2倍。HCC相关 具有一系列环境和感染病因，包括嗜肝病毒（HBV和HCV）感染， 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， 每一种都导致肝脏发病。80-90%的HCC患者存在肝硬化， 是最重要的风险因素HCC发病率在发达国家正在上升， 代谢综合征的患病率和较高的HCV感染率。肥胖、胰岛素抵抗和血脂异常， 已经成为NAFLD、肝硬化和HCC的重要原因。NASH和NAFLD是全球流行病 并且有证据表明，发生NASH相关HCC的风险>肝炎相关肝硬化。而 在美国，只有5-20%的NAFLD患者进展为NASH，这意味着2-5%的一般人群 有发生HCC的风险。由于在其初始阶段缺乏明显的症状，大多数HCC患者 被诊断为晚期疾病，存活时间<6个月。接受治疗的患者的中位生存期 只有6-20个月。5-局限期、区域期和远处期肝癌的年生存率分别为31.1%、10.7%， 和2.8%。肝移植、手术切除和消融提供了高反应率， 治疗早期HCC的潜力。然而，只有10%-23%的HCC患者被足够早地诊断出来。 对于这样的疗法。经动脉化疗栓塞或放射性栓塞是保留的患者的选择 肝功能和体力状态。晚期肝癌的细胞毒药物或化疗药物的全身化疗 联合用药的反应率只有10%-20%，而且不能延长总生存期。索拉非尼a 多种酪氨酸激酶的分子靶向抑制剂被批准用于HCC，但通过以下方式提高总生存率： 只有~3个月。瑞戈非尼，另一种多酪氨酸激酶抑制剂（TKI）被批准用于HCC患者， 肿瘤在索拉非尼上进展，也使存活仅约3个月。尽管生存益处有限 在用于HCC的多TKI中，还有几种处于临床开发中。免疫检查点免疫疗法 （派姆单抗或纳武单抗）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）（曲美木单抗）， 也在HCC的临床开发中。然而，仍然迫切需要新的、 有效的HCC治疗。HCC的病因和遗传异质性使得药物发现/开发 挑战性我们提出了一个表型qHTS策略，以确定新的探针或治疗线索，使用 HBV、HCV和NASH病因学的独特患者来源的HCC细胞系模型。

项目成果

Therapeutic evaluation of palbociclib and its compatibility with other chemotherapies for primary and recurrent nasopharyngeal carcinoma.

• DOI: 10.1186/s13046-020-01763-z
• 发表时间: 2020-11-26
• 期刊: Journal of experimental & clinical cancer research : CR
• 作者: Xue Z;Lui VWY;Li Y;Jia L;You C;Li X;Piao W;Yuan H;Khong PL;Lo KW;Cheung LWT;Lee VHF;Lee AWM;Tsao SW;Tsang CM
• 通讯作者: Tsang CM

TP53 R249S mutation in hepatic organoids captures the predisposing cancer risk.

肝癌中TP53 R249S突变捕获了易感性的癌症风险。

• DOI: 10.1002/hep.32802
• 发表时间: 2023-09-01
• 期刊: HEPATOLOGY
• 影响因子: 13.5
• 作者: Lam, Yin Kau;Yu, Jianqing;Huang, Hao;Ding, Xiaofan;Wong, Alissa M.;Leung, Howard H.;Chan, Anthony W.;Ng, Kelvin K.;Xu, Mingjing;Wang, Xin;Wong, Nathalie
• 通讯作者: Wong, Nathalie

Erlotinib sensitivity of MAPK1p.D321N mutation in head and neck squamous cell carcinoma.

头颈鳞状细胞癌中 MAPK1p.D321N 突变的厄洛替尼敏感性。

• DOI: 10.1038/s41525-020-0124-5
• 发表时间: 2020
• 期刊: NPJ genomic medicine
• 影响因子: 5.3
• 作者: Ngan,Hoi-Lam;Poon,PeonyHiuYan;Su,Yu-Xiong;Chan,JasonYingKuen;Lo,Kwok-Wai;Yeung,ChunKit;Liu,Yuchen;Wong,Eileen;Li,Hui;Lau,ChinWang;Piao,Wenying;Lui,VivianWaiYan
• 通讯作者: Lui,VivianWaiYan