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: 10687041
• 负责人: David John Tweardy
• 金额: $ 37.66万
• 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/10687041
• 关键词: Adjuvant; Adjuvant Study; Adjuvant Therapy; Adverse event; BAY 54-9085; Biological Availability; Cancer Center; Caring; Certification; Clinical; Clinical Laboratory Improvement Amendments; Collaborations; Computers; Development; Disease; Docking; Dose; Drug Kinetics; Effectiveness; Enrollment; Excision; Fatty Liver; HGF gene; Hepatocyte; Immunohistochemistry; Immunosuppression; 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; Recruitment Activity; Recurrence; Recurrent tumor; Resected; STAT3 gene; Safety; Schedule; Solid Neoplasm; Stat3 protein; Stromal Cells; Testing; Therapeutic; Time; Tissues; Toxic effect; Tumor Tissue; University of Texas M D Anderson Cancer Center; advanced disease; clinically relevant; cytokine; disorder control; experience; immune checkpoint blockade; immune resistance; improved; improved outcome; inhibitor; liver cancer model; liver inflammation; liver injury; mouse model; neoplastic cell; novel therapeutic intervention; participant enrollment; 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; translational goal; 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 虽然手术切除可能是针对早期肝细胞癌（HCC）的治疗方法 晚期疾病仅限于用索拉非尼，雷莫非尼或尼伏洛氏症治疗，以增加 生存3-4个月。即使在接受切除的患者中，5年内复发也发生在〜70％。 因此，迫切需要采取新的治疗策略来治疗晚期疾病并防止 术后复发。我们的长期翻译目标是改善晚期患者的预后 HCC阶段和术后HCC患者。超过90％的HCC病例在肝的情况下出现 损伤和炎症涉及多种细胞因子的产生，特别是肝细胞生长因子（HGF） 激活信号换能器和转录激活因子（Stat）3。STAT3是主调节器的IL-6 癌症的大多数关键标志和促成者及其激活发生在大约60％的HCC中 它是肿瘤复发的预测指标，并通过调节HCC中的免疫耐药性 髓样衍生的抑制细胞（MDSC）的发育，募集和免疫抑制活性。 我们的小组与一家临床阶段制药公司（TVARDI Therapeutics，Inc。）合作 基于计算机的对接和铅化合物优化策略，以识别TTI-101（C188-9），有效， STAT3的无毒和口服可生物利用的抑制剂。将TTI-101施用到发展肝脏的小鼠 脂肪变性和纤维化，然后是HCC（肝细胞特异性PTEN敲除小鼠）导致肿瘤生长的阻碍， 以及肝损伤和纤维化的明显减少。对实体瘤患者的第一阶段研究，包括 HCC，在MD Anderson的HCC通过剂量水平（DL）3显示不毒性，导致部分临床反应 在第一个HCC患者的DL2循环进行两个循环后，进入了试验。 TVARDI与部门合作 MD Anderson的病理学开发临床实验室改进修正案（CLIA）认证IHC测试 通过免疫组织化学（IHC）的PY-STAT3水平得分，该水平进一步发展为PY-STAT3 HCC肿瘤得分。我们假设STAT3有助于HCC肿瘤的生长和免疫耐药性， 以及HCC在肝脏炎症和纤维化的环境中的发展。我们进一步假设使用 与TTI-101这样的STAT3抑制剂的抑制剂，与 单独的标准疗法（Nivolumab）比尼伐单抗，将防止术后复发。在AIM 1中，我们 将在与Nivolumab结合使用时确定TTI-101的安全性和早期有效性 手术性不可切除的HCC患者。在AIM 2中，我们将确定PY-STAT3分数的实用性 HCC患者肿瘤或相邻的非肿瘤肝脏预测术后复发。在AIM 3中，我们将 确定TTI-101辅助治疗是否会减少HCC复发。该项目的影响将增加 患有高级阶段HCC患者的存活和接受HCC的复发率降低 手术切除。