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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：
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
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/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

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