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

德克萨斯大学 MD 安德森癌症中心 SPORE 在肝细胞癌中的应用

• 批准号: 10480071
• 负责人: LAURA BERETTA
• 金额: $ 227.83万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-25 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10480071
• 关键词: Address; Adjuvant; Affect; BAY 54-9085; Basic Science; Bile Acids; Biological Markers; Cancer Center; Cancer Etiology; Catchment Area; Cells; Cessation of life; Chronic Disease; Cirrhosis; Clinical Trials; County; Data; Death Rate; Diabetes Mellitus; Diagnosis; Early Intervention; Excision; FDA approved; Fatty Acids; Fibrosis; Geography; Goals; Hispanic Populations; Immune; Immune Targeting; Immunotherapy; Incidence; Liver; Liver Fibrosis; Malignant Neoplasms; Malignant neoplasm of liver; Malignant neoplasm of thyroid; Measures; Mexico; Neoadjuvant Therapy; Newly Diagnosed; Nivolumab; Obesity; Operative Surgical Procedures; Oral; Participant; Patients; Performance; Pharmaceutical Preparations; Placebos; Plasma; Postoperative Period; Primary carcinoma of the liver cells; Prognosis; Prospective Studies; Prospective cohort; Proteins; Recurrence; Resectable; Resected; Risk; STAT3 gene; Signal Transduction; South Texas; Survival Rate; Systemic Therapy; Target Populations; Texas; Therapeutic; Translational Research; Tyrosine Kinase Inhibitor; Underserved Population; United States; University of Texas M D Anderson Cancer Center; advanced disease; anti-PD-1; anti-tumor immune response; antitumor effect; arm; base; biobank; biomarker development; cancer diagnosis; cancer site; care seeking; checkpoint therapy; chronic liver disease; diabetic; elastography; gut microbiome; immune checkpoint; improved; improved outcome; inhibitor; innovation; liver biopsy; liver injury; liver transplantation; mortality; non-alcoholic; nonalcoholic steatohepatitis; patient population; prognostic significance; programmed cell death ligand 1; response; screening; trend; tumor; tumor behavior; tumor growth; vibration

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.

总体 - 摘要/摘要 德克萨斯大学医学博士安德森癌症中心孢子的总体目标 （HCC）是为了改善HCC患者的预后，并在早期降低HCC的死亡率 干涉。 HCC是全球癌症死亡的第二大原因，已诊断出854,000例新病例 2015年全球和810,000人死亡。全球新的HCC病例的发生率预计 到2035年，1,341,344例。在美国（美国），所有癌症的死亡率均下降 在过去10年中，大多数癌症部位，HCC死亡人数在所有癌症部位的最高率增加， HCC的发病率急剧增加，仅次于甲状腺癌。 HCC的负担并非同样 分布在整个美国，是在墨西哥 - 美国边境州的各州观察到的最高发病率。 德克萨斯州在HCC发病率中排名第二，与国家相比，每100,000例11.4箱的速度为11.4例 率为7.6。在德克萨斯州，与墨西哥接壤的县的西班牙裔人在美国的HCC比率最高 每100,000例诊断为37.5例。反映发生率上升的趋势，HCC患者的数量 每年在MD Anderson癌症中心寻求护理，从2013年的277名患者增加到580例 2017年的患者在最近5年中增加了2倍。 HCC的相对5年生存率为 16％。 HCC的预后不良是由于多种因素造成的：1）绝大多数HCC病例被诊断为 一个晚期，不适合治疗手术治疗（切除或肝移植）； 2）甚至 被切除的病例患有高复发率（2年内高达50％，在5年内70％）； 3）经常HCC 发生在晚期慢性肝病的背景下，尤其是肝硬化，限制治疗选择； 4） 仅FDA批准的第一线系统治疗是索拉非尼，总体可改善2.8个月 存活率和2％的惨淡响应率； 5）最近批准的第二行治疗是另一种 酪氨酸激酶抑制剂再氨基替尼和免疫疗法药物nivolumab，但总体上再次有所改善 生存和应答率非常低。在此孢子应用中，3个项目与3个核心将：1） 评估新辅助和辅助HCC设置中检查点疗法的效果，并确定最佳 与检查点疗法的组合，以增强抗肿瘤免疫反应； 2）确定 磷酸化STAT3作为术后复发的生物标志物的预后意义，并评估 TTI-101（C188-9），一种STAT3抑制剂在内部开发，作为术后辅助剂； 3）评估 Nivolumab和TTI-101在晚期HCC患者治疗中的组合； 4）执行 在德克萨斯州南部的肥胖和糖尿病西班牙裔肝纤维化进行广泛筛查，并识别非侵入性 纤维化阶段和进展的生物标志物在这个水位不足的人群中受到非酒精性影响很大的生物标志物 脂肪性肝炎和HCC。