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

总体--摘要/摘要 德克萨斯大学安德森癌症中心孢子治疗肝细胞癌的总体目标 (肝细胞癌)是通过早期治疗改善肝细胞癌患者的预后，降低死亡率。 干预。肝癌是全球第二大癌症死亡原因，新增854,000例确诊病例 全球范围内，2015年死亡人数为81万人。全球新的肝细胞癌病例预计将上升到 到2035年，1,341,344例。在美国，虽然所有癌症的死亡率加起来都有所下降 在过去的10年里，大多数癌症部位死于肝癌的人数是所有癌症部位中最高的。 肝癌发病率急剧上升，仅次于甲状腺癌。肝细胞癌的负担并不相同 分布在美国各地，发病率最高的是墨西哥-美国边境的各州。 德克萨斯州的肝癌发病率位居第二，5年发病率为11.4/10万，而全国为11.4/10万 这一比率为7.6。在德克萨斯州，与墨西哥接壤的县的拉美裔人患肝癌的比率是美国最高的， 每10万人中有37.5例确诊病例。反映出发病率上升的趋势，肝癌患者的数量 在MD安德森癌症中心寻求治疗的人数每年都在增加，从2013年的277名患者增加到580名 2017年的患者，比最近5年增加了2倍。肝细胞癌的相对5年生存率为 16%。肝细胞癌预后不良的原因是多方面的：1)绝大多数肝细胞癌患者是在 晚期，不适用于根治性手术治疗(切除或肝移植)；2)甚至 切除的病例复发率高(2年复发率高达50%，5年复发率高达70%)；3)肝细胞癌通常 发生在晚期慢性肝病，特别是肝硬变的背景下，限制了治疗选择；4) 只有FDA批准的一线系统疗法是索拉非尼，总体改善2.8个月 存活率和2%的不良反应率；5)最近批准的二线治疗是另一种 酪氨酸激酶抑制剂regorafenib和免疫治疗药物nivolumab，但总体上再次改善 存活率和应答率都很低。在这个孢子应用中，3个项目和3个核心将：1) 评估检查点治疗在新辅助和辅助肝癌环境中的效果，并确定最佳方案 联合检查点疗法以增强抗肿瘤免疫反应；2)确定 磷酸化STAT3作为术后复发生物标志物的预后意义及评价 TTI-101(C188-9)，一种自行开发的STAT3抑制剂，作为术后佐剂；3)评估 尼伏单抗联合TTI-101治疗晚期肝癌的临床研究 在德克萨斯州南部对肥胖和糖尿病拉美裔人群进行广泛的肝纤维化筛查，并确定非侵入性 高度受非酒精影响的服务不足人群纤维化分期和进展的生物标志物 脂肪性肝炎和肝癌。

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.