Cabozentinib based combination therapy for the treatment of hepatocellular carcinoma

项目摘要 摘要肝细胞癌是主要的原发性肝癌，其发病率在全球范围内呈上升趋势。 我们。肝细胞癌的治疗选择仍然非常有限，而且没有效果。慢性阻塞性肺疾病患者的总体存活率 晚期肝细胞癌仍然很差。卡波赞替尼是一种针对c-met、VEGFR1/2、 AXL、MER和ROS1。卡波赞替尼最近被FDA批准为治疗糖尿病的二线治疗方案 接受索拉非尼治疗的晚期肝癌患者。然而，分子机制 卡波先替尼治疗肝细胞癌的潜在疗效尚不清楚。在我们最近的研究中，我们调查了治疗 卡波赞替尼对14个人肝癌细胞系和4种癌基因驱动的肝癌的疗效 小鼠模型(c-Met/β-catenin、Akt/c-Met、Akt/RAS和c-Myc)。我们证明了卡波赞替尼 抑制肝癌细胞在IC50值可变的培养中的生长。卡波赞替尼的敏感度与 P-MET和p-ERK在肝癌细胞系中的表达。在体内，我们发现Cabozantinib治疗导致病情稳定 对c-Met/β-catenin和Akt/c-Met小鼠肝癌细胞的致病作用，但对AKT/RAS和c-Myc无明显作用 小鼠肝细胞癌。在细胞水平上，卡波扎替尼通过c-Met/β-连环蛋白和Akt/c-连环蛋白抑制肿瘤细胞的增殖。 Met肝细胞癌，AKT/RAS和c-Myc肝细胞癌均不表达。从机理上，我们证明了Cabozatintinib有效 抑制p-Met和p-ERK，诱导p21表达，但不影响p-AKT/mTOR信号转导通路。 Met/β-catenin和Akt/c-Met小鼠肝癌细胞株。重要的是，我们发现Cabozantinib治疗导致 C-Met/β-catenin肝癌中PD-L1表达增加。根据这些初步数据，我们假设 卡波赞替尼可与mTOR抑制剂或抗PD-L1抗体联合使用，以提高对 肝细胞癌。这一假设将在以下两个具体目标中得到检验。在目标1中，我们将调查 卡波赞替尼与MLN0128协同治疗肝癌；目的2.确定其治疗效果 卡波赞替尼与抗PD-L1抗体联合治疗小鼠肝癌的实验研究总而言之，该应用程序与 R03中试性实验和小型自给自足研究项目的资助机制。这项提议是第一个 卡波赞替尼为主的联合疗法治疗临床前肝癌的疗效观察 设置。我们的研究具有非常重要的意义，因为数据将为检查卡波赞替尼的联合用药提供支持 临床试验中的治疗。这一结果还可能为这一组合提供新的机制洞察力 用于选择可能受益于卡波赞替尼的肝细胞癌患者的治疗方法和可能的生物标志物 综合疗法。

PROJECT ABSTRACT Hepatocellular carcinoma (HCC) is the major type of primary liver cancer with increased incident rate the in the US. Treatment options for HCC are still very limited and not effective. The overall survival rate of patients with advanced HCC remains very poor. Cabozantinib is a multi-kinase inhibitor which targets c-MET, VEGFR1/2, AXL, MER and ROS1. Cabozantinib is recently approved by FDA as the second line treatment option for advanced HCC patients who has advanced with Sorafenib treatment. However, the molecular mechanisms underlying Cabozentinib efficacy in HCC is poorly understood. In our recent studies, we investigated therapeutic efficacy of Cabozantinib in a panel of 14 human HCC cell lines as well as 4 types of oncogene driven HCC mouse models (c-Met/β-Catenin, Akt/c-Met, Akt/Ras and c-Myc). We demonstrated that Cabozantinib suppressed HCC cell growth in culture with variable IC50 values. The sensitivities of Cabozantinib correlated with p-MET and p-ERK expression in HCC cell lines. In vivo, we found that Cabozantinib treatment led to stable disease in c-Met/β-Catenin and Akt/c-Met mouse HCCs, but it showed no efficacy towards AKT/Ras and c-Myc mouse HCCs. At the cellular levels, Cabozatintinib inhibited tumor cell proliferation in c-Met/β-Catenin and Akt/c- Met HCC, but not in AKT/Ras and c-Myc HCC. Mechanistically, we demonstrate that Cabozatintinib effectively inhibited p-MET and p-ERK, and induced p21 expression, but did not affect not p-AKT/mTOR signaling in c- Met/β-Catenin and Akt/c-Met mouse HCC. Importantly, we discovered that Cabozantinib treatment led to increased PD-L1 expression in c-Met/β-Catenin HCC. Based on these preliminary data, we hypothesize that Cabozantinib may be combined with mTOR inhibitors or anti-PD-L1 antibodies for improved efficacy against HCC. The hypothesis will be tested in the following two specific aims. In Aim 1, we will investigate whether Cabozantinib synergizes with MLN0128 for HCC treatment; and in Aim 2. To determine the therapeutic efficacy of combined Cabozantinib with anti-PD-L1 antibody in mouse HCC. Altogether, the application fits well with the R03 grant mechanism for pilot experiments and small, self-contained research projects. The proposal is the first to investigate the therapeutic efficacy of Cabozantinib based combination therapy against HCC in preclinical settings. Our studies are highly significant, as the data will provide support to examine Cabozantinib combination therapy in clinical trials. The results will also likely provide novel mechanistic insight into the combination therapies and possible biomarkers for selecting HCC patients who will likely benefit from Cabozantinib based combination therapies.