BASE:PREVENT PRECLINICAL DRUG DEVELOPMENT PROGRAM: PRECLINICAL EFFICACY&INTERMEDIATE BIOMARKERS TASK ORDER: TARGETING STAT3 TO PREVENT HEPATOCELLULAR

基础：预防临床前药物开发计划：临床前疗效

• 批准号: 10201174
• 负责人: DAVID TWEARDY
• 金额: $ 84.35万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10201174
• 关键词: Advanced Malignant Neoplasm; Affinity; Apoptosis; Binding; Biological Markers; Cancer Etiology; Canis familiaris; Cell Proliferation; Cessation of life; Cirrhosis; Country; Diabetes Mellitus; Dimerization; Dose; Epidemic; Family; Immune response; Incidence; Individual; Liver; Normal Cell; Obesity; Oral; Oral Administration; Patients; Peripheral Blood Mononuclear Cell; Phase I Clinical Trials; Phosphorylation; Plasma; Preclinical Drug Development; Prevention; Preventive; Preventive Intervention; Primary carcinoma of the liver cells; Program Development; Protein Tyrosine Kinase; Rattus; Research; Risk Factors; Role; Serum; Stat3 protein; Therapeutic; Toxic effect; Travel; United States; cancer type; diabetic; member; mortality; mouse model; non-alcoholic fatty liver disease; nonalcoholic steatohepatitis; preclinical efficacy; prevent; small molecule; src Homology Region 2 Domain; transcription factor; trend

Non-alcoholic steatohepatitis (NASH) is a type of non-alcoholic fatty liver disease (NAFLD) that primarily arises in obese and diabetic individuals. About a quarter of people with NASH ultimately develop cirrhosis, which is the main risk factor for hepatocellular carcinoma (HCC). HCC is the second cause of cancer-related mortality worldwide, and HCC associated with NASH is one of the fastest growing causes of cancer-related deaths in the United States, due in large part to the burgeoning obesity and diabetes epidemics. Prevention is, therefore, an urgent unmet need and an important priority to reverse the current trend of increasing incidence in this country. Signal transducer and activator of transcription 3 (STAT3) is one of the seven members of a family of transcription factors that regulates cell proliferation, differentiation, apoptosis, and the immune response. Although the activation of STAT3 is transient and highly regulated in normal cells, it is constitutively active in several types of cancer, including 50% of HCC. Recent findings from Jung et al. support a role for STAT3 in NASH-associated HCC and suggest that targeting STAT3 with the small molecule C188-9 (also known as TTI-101) could be a successful preventive intervention. TTI-101, developed by Dr. David Tweardy and colleagues and licensed to Tvardi Therapeutics, binds to the SH2 domain of STAT3 with high affinity and inhibits the protein’s dimerization and phosphorylation. It does not target other tyrosine kinases, provides excellent plasma exposure following oral administration, and produces no detectable toxicity when administered for a period of 28 days in rats and dogs. It is currently being evaluated in a Phase I clinical trial in patients with advanced cancers. The purpose of this Task Order is to evaluate TTI-101 for the prevention of HCC associated with NASH in a mouse of model of NASH-associated HCC.

非酒精性脂肪性肝炎（NASH）是一种非酒精性脂肪性肝病（NAFLD），主要发生在肥胖和糖尿病患者中。大约四分之一的NASH患者最终发展为肝硬化，这是肝细胞癌（HCC）的主要风险因素。HCC是全球癌症相关死亡的第二大原因，并且与NASH相关的HCC是美国癌症相关死亡增长最快的原因之一，这在很大程度上是由于肥胖和糖尿病流行的迅速发展。因此，预防是一项尚未得到满足的迫切需要，也是扭转该国目前发病率上升趋势的一个重要优先事项。 信号转导子和转录激活子3（STAT 3）是调节细胞增殖、分化、凋亡和免疫应答的转录因子家族的七个成员之一。尽管STAT 3的激活在正常细胞中是短暂的和高度调节的，但它在几种类型的癌症中具有组成性活性，包括50%的HCC。Jung等人最近的研究结果支持STAT 3在NASH相关HCC中的作用，并表明用小分子C188-9（也称为TTI-101）靶向STAT 3可能是一种成功的预防性干预。 TTI-101由大卫Tweardy博士及其同事开发，并授权给Tvardi Therapeutics，以高亲和力结合STAT 3的SH 2结构域，并抑制蛋白质的二聚化和磷酸化。它不靶向其他酪氨酸激酶，经口给药后提供极好的血浆暴露，在大鼠和犬中给药28天后未产生可检测到的毒性。目前正在晚期癌症患者中进行I期临床试验。本任务指令旨在评价TTI-101在NASH相关HCC小鼠模型中预防NASH相关HCC的作用。