The University of Texas MD Anderson Cancer Center SPORE in Hepatocellular Carcinoma

总体-总结/摘要 德克萨斯大学MD安德森癌症中心SPORE在肝细胞癌方面的总体目标 (HCC)是通过早期治疗改善HCC患者的预后，降低HCC的死亡率。 干预HCC是全球癌症死亡的第二大原因，有854，000例新诊断病例 2015年全球死亡81万人。预计全球新发HCC病例的发病率将上升至 到2035年将有1，341，344例。在美国，而所有癌症的死亡率都有所下降， 在过去的10年中，对于大多数癌症部位，HCC的死亡率在所有癌症部位中以最高的速度增加， 肝癌发病率急剧上升，仅次于甲状腺癌。HCC的负担并不相等 分布在美国各地，发病率最高的是墨西哥-美国边境的州。 德克萨斯州在HCC发病率方面排名第二，与全国相比，5年发病率为每10万人11.4例 率7.6。在得克萨斯州，与墨西哥接壤的县的西班牙裔人的HCC发病率在美国最高， 每10万人中有37.5例确诊病例。反映了发病率上升的趋势，肝癌患者人数 在MD安德森癌症中心寻求治疗的患者每年都在增加，从2013年的277名患者增加到580名 2017年的患者人数比最近5年增加了2倍。HCC的相对5年生存率为 百分之十六HCC预后差是由于多种因素：1）绝大多数HCC病例诊断为 晚期，不适合治愈性手术治疗（切除或肝移植）; 2）甚至 切除的病例复发率高（2年内高达50%，5年内高达70%）; 3）HCC经常 发生在晚期慢性肝病，特别是肝硬化的背景下，限制了治疗选择; 4） 只有FDA批准的一线全身治疗是索拉非尼， 存活率和2%的令人沮丧的反应率;和5）最近批准的二线治疗是另一个 酪氨酸激酶抑制剂regorafenib和免疫治疗药物nivolumab，但再次改善整体 存活率和反应率都很低。在这个SPORE应用程序中，3个项目与3个核心一起将：1） 评估检查点治疗在新辅助和辅助HCC环境中的效果， 与检查点治疗剂的组合以增强抗肿瘤免疫应答; 2）确定免疫应答; 磷酸化STAT3作为术后复发的生物标志物的预后意义， TTI-101（C188 - 9），一种内部开发的STAT3抑制剂，作为术后佐剂; 3）评估 纳武单抗和TTI-101的组合治疗晚期HCC患者; 4）进行 在德克萨斯州南部的肥胖和糖尿病西班牙裔中广泛筛查肝纤维化，并确定非侵入性 纤维化阶段和进展的生物标志物在这个服务不足的人群中高度受非酒精性 脂肪性肝炎和HCC。

Overall - SUMMARY/ABSTRACT The overall goal of the University of Texas MD Anderson Cancer Center SPORE in Hepatocellular Carcinoma (HCC) is to improve outcomes for HCC patients and reduce the mortality rates of HCC through early intervention. HCC is the 2nd leading cause of cancer death worldwide with 854,000 new cases diagnosed globally and 810,000 deaths in 2015. The incidence of new HCC cases globally is projected to rise to 1,341,344 cases by 2035. In the United States (U.S.), while death rates declined for all cancers combined and for most cancer sites in the past 10 years, deaths from HCC increased at the highest rate of all cancer sites, and HCC incidence rates increased sharply, second only to thyroid cancer. The burden of HCC is not equally distributed throughout the U.S., the highest incidence being observed in States on the Mexico-US Border. Texas ranks second in incidence of HCC, with a 5-year rate of 11.4 cases per 100,000 compared to the nation rate of 7.6. Within Texas, Hispanics in counties bordering Mexico have the highest rates of HCC in the U.S., with 37.5 diagnosed cases per 100,000. Reflecting the rising incidence trends, the number of HCC patients seeking care at MD Anderson Cancer Center has increased every year, from 277 patients in 2013 to 580 patients in 2017, a 2-fold increase over the most recent 5 years. The relative 5-year survival rate for HCC is 16%. The poor prognosis of HCC is due to multiple factors: 1) the vast majority of HCC cases are diagnosed at an advanced stage, not amenable to curative surgical treatment (resection or liver transplantation); 2) even resected cases suffer from high rates of recurrence (up to 50% in 2 years and 70% in 5 years); 3) HCC often occurs in the context of advanced chronic liver disease, cirrhosis in particular, limiting treatment options; 4) the only FDA-approved first line systemic therapy is sorafenib which offers a 2.8 months improvement in overall survival and a dismal response rate of 2%; and 5) the recently approved second line therapy are another tyrosine kinase inhibitor regorafenib and the immunotherapy drug nivolumab, but again improvement in overall survival and response rates are very low. In this SPORE application, 3 projects together with 3 cores will: 1) evaluate the effect of checkpoint therapy in neoadjuvant and adjuvant HCC settings and determine optimal combinations with checkpoint therapeutics to enhance the anti-tumor immune response; 2) determine the prognostic significance of phosphorylated STAT3 as a biomarker for postoperative recurrence and evaluate TTI-101 (C188-9), a STAT3 inhibitor developed in-house, as a post-operative adjuvant; 3) evaluate the combination of nivolumab and TTI-101 in the treatment of patients with advanced stage HCC; 4) perform extensive screening for liver fibrosis in obese and diabetic Hispanics in South Texas, and identify non-invasive biomarkers of fibrosis stage and progression in this underserved population highly affected by non-alcoholic steatohepatitis and HCC.