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

基本信息

批准号：
10480100
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
项目类别：
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/10480100
关键词：
Adjuvant Adjuvant Study Adjuvant Therapy Adverse event BAY 54-9085 Cancer Center Caring 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 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 liver cancer model 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 translational goal tumor tumor growth

项目摘要

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/摘要虽然手术切除对于早期肝细胞癌 (HCC) 有潜在治愈作用，但晚期疾病仅限于索拉非尼、瑞戈非尼或纳武单抗治疗，这些治疗会增加存活3-4个月。即使接受切除的患者，5年内复发的概率也高达70%左右。因此，迫切需要新的治疗策略来治疗晚期疾病并预防术后复发。我们的长期转化目标是改善晚期患者的治疗结果分期 HCC 和术后 HCC 患者。超过 90% 的 HCC 病例发生在肝病背景下损伤和炎症，涉及多种细胞因子的产生，尤其是肝细胞生长因子 (HGF) 和 IL-6 激活信号转导子和转录激活子 (STAT) 3。STAT3 是大多数癌症的关键标志和推动因素及其激活发生在大约 60% 的 HCC 中它是肿瘤复发的预测因子，并通过调节 HCC 的免疫抵抗力来促进 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。我们的团队与一家临床阶段的制药公司（Tvardi Therapeutics, Inc.）合作，使用基于计算机的对接和先导化合物优化策略来识别 TTI-101 (C188-9)，这是一种有效的、无毒且口服生物可利用的 STAT3 抑制剂。对发育出肝脏的小鼠施用 TTI-101 脂肪变性和纤维化导致 HCC（肝细胞特异性 Pten 敲除小鼠）导致肿瘤生长停滞，以及显着减少肝损伤和纤维化。针对实体瘤患者的 I 期研究，包括 MD 安德森中心的 HCC 在剂量水平 (DL) 3 下未显示出毒性，并产生了部分临床反应第一个 HCC 患者在 DL2 两个周期后进入试验。 Tvardi 与以下部门合作 MD 安德森病理学中心将开发临床实验室改进修正案 (CLIA) 认证的 IHC 测试并通过免疫组织化学 (IHC) 对 pY-STAT3 水平进行评分，该评分进一步发展为 pY-STAT3 HCC 肿瘤的评分。我们假设 STAT3 有助于 HCC 肿瘤生长和免疫抵抗，以及肝脏炎症和纤维化背景下肝癌的发展。我们进一步假设使用 STAT3 抑制剂（例如 TTI-101）与联合用药治疗晚期 HCC 会更有效标准疗法（纳武单抗）比单独使用纳武单抗更能预防术后复发。在目标 1 中，我们将确定 TTI-101 与纳武单抗联合使用时的安全性和早期有效性患有无法手术切除的 HCC 的患者。在目标 2 中，我们将确定 pY-STAT3 分数的效用 HCC 患者肿瘤或邻近非肿瘤肝脏预测术后复发。在目标 3 中，我们将确定 TTI-101 辅助治疗是否可以减少 HCC 复发。该项目的影响力将会增强晚期 HCC 患者的生存率和接受化疗的患者的 HCC 复发率降低手术切除。