Mechanisms of TWIST1-induced sorafenib resistance in liver CA

TWIST1诱导肝CA索拉非尼耐药的机制

基本信息

批准号：
8785775
负责人：
Kekoa Taparra
金额：
$ 4.27万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-08-01 至 2017-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8785775
关键词：
Address Antibodies Attention BAY 54-9085 BHLH Protein Binding Sites Bioinformatics Biological Assay Bypass Cancer Etiology Cancer Patient Cell Line Cells Cessation of life Clinical Cytotoxic agent Data Diagnosis Drug Targeting Drug resistance ERBB3 gene Epithelial Epithelial Cells FDA approved FLT3 gene Future Genetic Goals Growth Histologic In Vitro Incidence Lead Link Liver Liver Cirrhosis Liver neoplasms Luciferases Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of liver Mediating Mesenchymal Modeling Molecular Mus Oncogene Proteins Operative Surgical Procedures Oral Pathologist Pathway interactions Patients Pharmaceutical Preparations Phase Phase III Clinical Trials Phenotype Phosphoproteins Platelet-Derived Growth Factor Receptor Primary carcinoma of the liver cells Process Promoter Regions Protein Dephosphorylation Protein Tyrosine Kinase Proteins Proto-Oncogene Protein c-kit Receptor Protein-Tyrosine Kinases Refractory Regulation Reporter Research Resistance Role Sampling Signal Pathway Signal Transduction Signaling Molecule Staging Stat3 protein Systemic Therapy TWIST1 gene Techniques Therapeutic Agents Time Transcriptional Activation Transcriptional Regulation Tumor-Derived Up-Regulation Vascular Endothelial Growth Factor Receptor cancer therapy drug sensitivity genetic profiling hepatocellular carcinoma cell line improved in vivo in vivo Model inhibitor/antagonist liver inflammation migration novel outcome forecast overexpression promoter public health relevance raf Kinases research study resistance mechanism response standard of care transcription factor tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): Hepatocellular carcinoma (HCC) is a major cause of cancer-related death worldwide with the fastest rising incidence of all cancers at present time. Sorafenib is an oral multikinase inhibitor that holds as the only consistently efficacious systemic therapeutic agent in the treatment of advanced staged HCC as demonstrated in recent Phase III clinical trials. Patient data reveals frequent resistance to sorafenib by means of either acquired resistance, in which the tumor progresses during treatment despite initial drug sensitivity, or de novo resistance, in which a tumor is refractory at the onset of treatment. Interestingly, TWIST1 expression also correlates with poor prognosis and advanced stages among HCC patients. TWIST1 also shows a correlation with resistance to other systemic therapies and my preliminary data suggests TWIST1 can confer sorafenib resistance to HCC cells. The precise pathways that TWIST1 may influence to cause sorafenib resistance have not been studied thus far. Preliminary data suggests that TWIST1 may be activated downstream of Signal Transducer and Activator of Transcription 3 (STAT3) and once activated may initiate a variety of signaling cascades to induce sorafenib resistance. Phosphoprotein RTK antibody array data suggests that PDGFR, HER3, and EphA3 may be upregulated by TWIST1 to mediate sorafenib resistance in HCC cell lines. As such, the mechanisms by which TWIST1 may mediate sorafenib resistance include reactivation/overexpression of the sorafenib target (i.e. PDGFR) or activation of bypass effector oncoproteins (i.e. HER3 or EphA3) in which a parallel signaling molecule activates downstream targets necessary for drug resistance. The experiments outlined in this F31 application aim to causally identify and mechanistically describe the pathways involved in TWIST1-induced sorafenib resistance and credential a novel STAT3-TWIST1 axis by which HCC tumors develop sorafenib resistance. First, STAT3 will be assessed for direct transcriptional activation of TWIST1 and the role of TWIST1 in sorafenib resistance. Secondly, candidate receptor tyrosine kinases will be analyzed to causally identify sorafenib resistance mechanisms. Thirdly, our novel TWIST1-inducible murine autochthonous liver tumor model will be utilized to evaluate TWIST1-induced sorafenib resistance in vivo and validate mechanisms identified with HCC cells in vitro.

描述（由申请人提供）：肝细胞癌（HCC）是全世界癌症相关死亡的主要原因，目前是所有癌症中发病率上升最快的。索拉非尼是一种口服多激酶抑制剂，是唯一持续有效的全身性药物最近的 III 期临床试验证明了治疗晚期 HCC 的治疗剂。患者数据显示，索拉非尼经常产生耐药性，要么是获得性耐药，即尽管最初对药物敏感，但肿瘤在治疗过程中进展；要么是新生耐药，即肿瘤在治疗开始时难以治疗。有趣的是，TWIST1 表达还与 HCC 患者的不良预后和晚期阶段相关。 TWIST1 还显示出与其他全身疗法耐药性的相关性，我的初步数据表明 TWIST1 可以赋予索拉非尼对 HCC 细胞的耐药性。迄今为止，尚未研究 TWIST1 可能影响导致索拉非尼耐药的确切途径。初步数据表明，TWIST1 可能在信号转导器和转录激活子 3 (STAT3) 下游被激活，一旦激活可能启动多种信号级联反应，从而诱导索拉非尼耐药。磷蛋白 RTK 抗体阵列数据表明，TWIST1 可能上调 PDGFR、HER3 和 EphA3，从而介导 HCC 细胞系中的索拉非尼耐药。因此，TWIST1可能介导索拉非尼耐药的机制包括索拉非尼靶点（即PDGFR）的重新激活/过度表达或旁路效应癌蛋白（即HER3或EphA3）的激活，其中并行信号分子激活耐药所需的下游靶点。该 F31 申请中概述的实验旨在因果性地识别和机械地描述 TWIST1 诱导的索拉非尼耐药所涉及的途径，并证明 HCC 肿瘤通过该轴产生索拉非尼耐药的新型 STAT3-TWIST1 轴。首先，将评估 STAT3 对 TWIST1 的直接转录激活以及 TWIST1 在索拉非尼耐药中的作用。其次，将分析候选受体酪氨酸激酶，以确定索拉非尼耐药机制的因果关系。第三，我们的新型 TWIST1 诱导型小鼠原地肝肿瘤模型将用于评估 TWIST1 诱导的索拉非尼体内耐药性，并验证体外 HCC 细胞确定的机制。