Project 2: Targeting STAT3 with an Oral Small Molecule to Treat HCC

项目 2：用口服小分子靶向 STAT3 治疗 HCC

• 批准号: 10246497
• 负责人: David John Tweardy
• 金额: $ 55.63万
• 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/10246497
• 关键词: Adjuvant; Adjuvant Study; Adjuvant Therapy; Adverse event; BAY 54-9085; Bioavailable; Cancer Center; Caring; Clinical; Clinical Laboratory Improvement Amendments; Collaborations; Computers; Development; Disease; Docking; Dose; Drug Kinetics; Effectiveness; Enrollment; Excision; Fatty Liver; Goals; HGF gene; Hepatocyte; Immunohistochemistry; Inflammation; Interleukin-6; Knockout Mice; Lead; Liver; Liver Fibrosis; Malignant Neoplasms; Measurement; Measures; Mus; Myeloid-derived suppressor cells; Nivolumab; Operative Surgical Procedures; Oral; Partial Hepatectomy; Pathology; Patients; Peripheral Blood Mononuclear Cell; Pharmacodynamics; Pharmacologic Substance; Phase; Plasma; Postoperative Period; Primary carcinoma of the liver cells; Production; Progression-Free Survivals; Proteins; RNA; Recurrence; Resected; STAT3 gene; Safety; Schedule; Solid Neoplasm; Stat3 protein; Stromal Cells; Testing; Therapeutic; Time; Toxic effect; Tumor Tissue; University of Texas M D Anderson Cancer Center; advanced disease; base; clinically relevant; cytokine; disorder control; experience; immune checkpoint blockade; immune resistance; improved; improved outcome; inhibitor/antagonist; liver inflammation; liver injury; mouse model; neoplastic cell; novel therapeutic intervention; pharmacokinetics and pharmacodynamics; phase 1 study; phase I trial; postoperative recovery; prevent; primary endpoint; recruit; response; secondary endpoint; side effect; small molecule; small molecule inhibitor; tumor; tumor growth

Project 2 - SUMMARY/ABSTRACT While surgical resection is potentially curative for early stage hepatocellular carcinoma (HCC), care of advanced stage disease is limited to treatment with sorafenib, regorafenib, or nivolumab which increase survival by 3-4 months. Even in patients who undergo resection, recurrence within 5 years occurs in ~70%. Therefore, there is an urgent need for new therapeutic strategies to treat advanced disease and to prevent postoperative recurrence. Our long-term translational goal is to improve outcomes in patients with advanced stage HCC and in post-operative HCC patients. More than 90% of HCC cases arise in the setting of hepatic injury and inflammation, which involve production of several cytokines, notably hepatocyte growth factor (HGF) and IL-6 that activate signal transducer and activator of transcription (STAT) 3. STAT3 is a master regulator of most of the key hallmarks and enablers of cancer and its activation occurs in approximately 60% of HCCs where it is a predictor of tumor recurrence and contributes to immune resistance in HCC by regulating the development, recruitment, and the immunosuppressive activity of myeloid-derived suppressor cells (MDSCs). Our group, in collaboration with a clinical-stage pharmaceutical firm (Tvardi Therapeutics, Inc.), used computer-based docking and lead-compound optimization strategies to identify TTI-101 (C188-9), a potent, non-toxic and orally bioavailable inhibitor of STAT3. Administration of TTI-101 to mice that develop liver steatosis and fibrosis followed by HCC (hepatocyte-specific Pten knockout mice) led to arrest of tumor growth, as well as marked reduction in liver injury and fibrosis. A Phase I study of patients with solid tumors, including HCC, at MD Anderson showed no toxicity through dose level (DL) 3 and resulted in a partial clinical response after two cycles at DL2 in the first HCC patient entered into the trial. Tvardi collaborated with the Department of Pathology at MD Anderson to develop a clinical laboratory improvement amendments (CLIA)-certified IHC test and score for pY-STAT3 levels by immunohistochemistry (IHC), which was further developed into a pY-STAT3 score for HCC tumors. We hypothesize that STAT3 contributes to HCC tumor growth and immune resistance, as well as HCC development in the setting of liver inflammation and fibrosis. We hypothesize further that use of a STAT3 inhibitor, such as TTI-101, will be more effective at treating advanced HCC when combined with standard therapy (nivolumab) than nivolumab alone and will prevent postoperative recurrence. In Aim 1, we will determine the safety and early effectiveness of TTI-101 when used in combination with nivolumab in patients with surgically non-resectable HCC. In Aim 2, we will determine the utility of the pY-STAT3 score of HCC patient tumors or adjacent non-tumoral liver in predicting postoperative recurrence. In Aim 3, we will determine if TTI-101 adjuvant therapy reduces HCC recurrence. The impact of this project would be increased survival of patients with advanced stage HCC and reduced recurrence of HCC in patients who undergo surgical resection.

项目2 -摘要/摘要 虽然手术切除可能治愈早期肝细胞癌（HCC），但 晚期疾病限于用索拉非尼、瑞格非尼或纳武单抗治疗， 存活3-4个月。即使在接受切除术的患者中，5年内复发率也约为70%。 因此，迫切需要新的治疗策略来治疗晚期疾病并预防癌症。 术后复发我们的长期转化目标是改善晚期乳腺癌患者的预后。 分期HCC和术后HCC患者。超过90%的HCC病例发生在肝硬化背景下。 损伤和炎症，涉及几种细胞因子的产生，特别是肝细胞生长因子（HGF） 和激活信号转导子和转录激活子（STAT）3的IL-6。STAT 3是一个主调节器， 癌症及其活化的大多数关键标志和促成因素发生在约60%的HCC中 它是肿瘤复发的预测因子，并通过调节免疫调节因子而导致HCC的免疫抵抗。 骨髓源性抑制细胞（MDSC）的发育、募集和免疫抑制活性。 我们的团队与临床阶段制药公司（Tvardi Therapeutics，Inc.）合作，使用 基于计算机的对接和铅化合物优化策略，以确定TTI-101（C188-9），一种有效的， 无毒且口服生物可利用的STAT 3抑制剂。将TTI-101施用于发育肝脏的小鼠 脂肪变性和纤维化，随后HCC（肝细胞特异性Pten敲除小鼠）导致肿瘤生长停滞， 以及肝损伤和纤维化的显著减少。实体瘤患者的I期研究，包括 MD安德森的HCC在剂量水平（DL）3中未显示毒性，并导致部分临床应答 在第一个进入试验的HCC患者的DL 2两个周期后。Tvardi与教育部合作， MD安德森病理学中心开发临床实验室改进修正案（CLIA）认证的IHC检测 并通过免疫组织化学（IHC）对pY-STAT 3水平进行评分，其进一步发展为pY-STAT 3免疫组化。 肝癌肿瘤评分。我们假设STAT 3有助于HCC肿瘤生长和免疫抵抗， 以及在肝脏炎症和纤维化的情况下HCC的发展。我们进一步假设， STAT 3抑制剂，如TTI-101，在联合治疗晚期HCC时， 标准疗法（nivolumab）比单独的nivolumab更有效，并且将防止术后复发。目标1： 将确定TTI-101与纳武利尤单抗联合使用时的安全性和早期有效性， 手术不可切除的HCC患者。在目标2中，我们将确定pY-STAT 3评分的效用， HCC患者肿瘤或邻近非肿瘤肝预测术后复发。在目标3中，我们 确定TTI-101辅助治疗是否减少HCC复发。该项目的影响力将得到加强 晚期肝癌患者的生存率和接受化疗患者的肝癌复发率降低 手术切除