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

项目2--摘要/摘要 虽然手术切除对早期肝细胞癌有潜在的治愈作用，但 晚期疾病仅限于使用索拉非尼、雷戈拉非尼或尼伏卢单抗治疗，这些药物增加了 存活时间延长3-4个月。即使在接受切除的患者中，5年内复发的比例也在70%左右。 因此，迫切需要新的治疗策略来治疗晚期疾病和预防 术后复发。我们的长期目标是改善晚期癌症患者的预后 在肝细胞癌分期和术后肝细胞癌患者中。90%以上的肝细胞癌病例发生在肝脏 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IL-6激活信号转导和转录激活因子(STAT)3。STAT3是信号转导和转录激活因子(STAT)的主要调节者 大多数癌症的关键标志和致癌因素及其激活发生在大约60%的肝癌中 其中，它是肿瘤复发的预测因子，并通过调节 髓系来源的抑制细胞(MDSCs)的发展、募集和免疫抑制活性。 我们的团队与临床阶段的制药公司(Tvardi Treateutics，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)， 无毒、口服生物可利用的STAT3抑制剂。TTI-101对发育肝小鼠的作用 脂肪变性和纤维化之后的肝癌(肝细胞特异性Pten基因敲除小鼠)导致肿瘤生长停止， 以及明显减少肝脏损伤和纤维化。实体肿瘤患者的I期研究，包括 在MD Anderson，肝细胞癌通过剂量水平(DL)3显示无毒性，并导致部分临床反应 在DL2两个周期后，第一个肝细胞癌患者进入试验。Tvardi与美国司法部合作 MD Anderson将开发临床实验室改进修正案(CLIA)认证的IHC测试 免疫组织化学(IHC)对Py-STAT3进行评分，进一步发展为Py-STAT3 为肝细胞癌肿瘤评分。我们假设STAT3有助于肝癌肿瘤的生长和免疫耐药， 以及肝细胞癌在肝脏炎症和纤维化的背景下的发展。我们进一步假设使用 联合应用STAT3抑制剂，如TTI-101，将更有效地治疗晚期肝癌 标准治疗(Nivolumab)优于单独应用nivolumab，并可防止术后复发。在目标1中，我们 将确定TTI-101与nivolumab联合使用时的安全性和早期有效性 不能手术切除的肝细胞癌患者。在目标2中，我们将确定Py-STAT3评分在 肝癌患者肿瘤或邻近非肿瘤肝脏对术后复发的预测价值。在《目标3》中，我们将 确定TTI-101辅助治疗是否可减少肝癌复发。这个项目的影响将会增加 晚期肝细胞癌患者的存活率和术后肝细胞癌复发的减少 手术切除。

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.