Cabozentinib based combination therapy for the treatment of hepatocellular carcinoma

项目摘要 肝细胞癌（HCC）是原发性肝癌的主要类型， 我们HCC的治疗选择仍然非常有限且无效。患者的总生存率 晚期HCC仍然非常差。卡博替尼是一种多激酶抑制剂，其靶向c-MET、VEGF 1/2、 AXL、MER和ROS 1。卡博替尼最近被FDA批准作为用于治疗糖尿病的二线治疗选择。 索拉非尼治疗后进展的晚期HCC患者。然而，分子机制 对卡博替尼在HCC中的潜在功效知之甚少。在我们最近的研究中， 卡博替尼在一组14种人HCC细胞系以及4种癌基因驱动的HCC中的功效 小鼠模型（c-Met/β-Catenin、Akt/c-Met、Akt/Ras和c-Myc）。我们证明了卡博替尼 在培养物中以可变的IC 50值抑制HCC细胞生长。卡博替尼的敏感性与 HCC细胞系中的p-MET和p-ERK表达。在体内，我们发现卡博替尼治疗导致稳定的 在c-Met/β-Catenin和Akt/c-Met小鼠肝癌中，它对c-Met/β-Catenin和Akt/c-Met小鼠肝癌中的疾病显示出有效性，但对AKT/Ras和c-Myc没有显示出有效性 小鼠肝癌。在细胞水平，卡博沙替尼抑制c-Met/β-连环蛋白和Akt/c- 在AKT/Ras和c-Myc HCC中未见表达。从机制上讲，我们证明卡博沙替尼有效地 抑制p-MET和p-ERK，并诱导p21表达，但不影响c-Akt/mTOR信号转导。 Met/β-连环蛋白和Akt/c-Met小鼠HCC。重要的是，我们发现卡博替尼治疗导致 c-Met/β-Catenin HCC中PD-L1表达增加。根据这些初步数据，我们假设， 卡博替尼可以与mTOR抑制剂或抗PD-L1抗体组合，以改善抗肿瘤的功效。 HCC。将在以下两个具体目标中检验这一假设。在目标1中，我们将研究 卡博替尼与MLN 0128协同用于HCC治疗;以及在目的2中。确定治疗效果 卡博替尼与抗PD-L1抗体联合治疗小鼠HCC。总之，该应用程序与 R 03试点实验和小型独立研究项目的赠款机制。该建议是第一个 在临床前研究基于卡博替尼的联合疗法对HCC的治疗功效， 设置.我们的研究是非常重要的，因为数据将为检查卡博替尼组合提供支持。 临床试验中的治疗。这些结果也可能为这种组合提供新的机理见解 用于选择可能受益于基于卡博替尼的HCC患者的治疗和可能的生物标志物 联合治疗

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.