DCLK1 is a Novel Molecular Target in Hepatocellular Carcinoma

DCLK1 是肝细胞癌的新型分子靶点

基本信息

批准号：
10046273
负责人：
Courtney Wayne Houchen
金额：
--
依托单位：
OKLAHOMA CITY VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-10-01 至 2022-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10046273
关键词：
Ablation Alcoholic Liver Cirrhosis Antineoplastic Agents BAY 54-9085 Biological Assay Biology Cancer Burden Cancer Etiology Cause of Death Cell Culture Techniques Cell Cycle Progression Cell Lineage Cells Cessation of life Characteristics Chronic Hepatitis Chronic viral hepatitis Cirrhosis Colon Data Development Diabetes Mellitus Diagnosis Drug usage Epithelial Epithelial Cells Etiology Excision Exposure to FDA approved FUS-1 Protein Fatty Liver Goals Growth Health Healthcare Hepatic Hepatitis C virus Hepatocyte Hepatotoxicity Human Immunodeficient Mouse Incidence Inflammation Injury Intestines Investigation Liver Liver diseases Liver neoplasms Luciferases Malignant Neoplasms Malignant neoplasm of liver Malignant neoplasm of pancreas Medical Mesenchymal Metabolic Diseases Microtubule Bundle Molecular Molecular Target Mus Mutation Neoplasm Metastasis Nodule Nude Mice Obesity Oncogenes Oncogenic Operative Surgical Procedures Organ Pancreas Pathway interactions Patients Pattern Pharmaceutical Preparations Phosphotransferases Prevalence Primary carcinoma of the liver cells Prognosis Proteins Protocols documentation Public Health RNA Interference Radiation Relapse Reporter Resistance Risk Risk Factors Role S100A9 gene Series Serum Signal Pathway Signal Transduction Signal Transduction Pathway Small Interfering RNA Solid Neoplasm Survival Rate TNF gene Testing Therapeutic Agents Transforming Growth Factor beta Transitional Cell Carcinoma Transplantation Tumor Stem Cells Tumor Suppressor Genes Tumor-Derived Up-Regulation Veterans Virus Diseases Xenograft Model beta catenin c-myc Genes cancer initiation cell motility chemotherapy disease diagnosis efficacy evaluation gamma secretase genotoxicity hepatoma cell hepatotoxin improved inhibitor/antagonist knock-down liver injury liver transplantation migration mortality mouse model neoplastic new therapeutic target non-alcoholic non-alcoholic fatty liver disease nonalcoholic steatohepatitis notch protein novel novel therapeutics overexpression patient derived xenograft model prevent programs self-renewal small hairpin RNA stem cell population therapeutically effective trend tumor tumor growth tumor initiation tumor progression tumor xenograft tumorigenesis tumorigenic

项目摘要

Hepatocellular carcinoma (HCC), a major form of liver cancer, is the second most common cause of cancer-related deaths worldwide. Its prognosis is poor, with a 5-year survival rate of less than 15%. The national prevalence and mortality due to cirrhosis and HCC in VA health care users have been increased by 2.5 to 3-fold during the last decade. The predicted increasing trend of HCC incidence and HCC-related deaths in the US veterans group remains alarming. Chronic hepatitis, alcoholic cirrhosis, fatty liver, and exposure to hepatotoxins are the major risk factors for HCC development. The risk of HCC increases strikingly in HCV carriers with diabetes and obesity. Thus, HCC is a major cause of deaths and veterans’ health issue. A single FDA-approved medical therapy for HCC, sorafenib only extends survival by approximately 3 months. Curative surgical options include hepatic resection and liver transplantation. However, very few patients are surgical candidates due to a late diagnosis of HCC. One of the major obstacles preventing the development of effective therapeutic agents is due to the potential existence of tumor stem cells (TSCs) in HCC. Most tumors contain a small percentage (1% to 2%) of TSC population that are believed to be responsible for resistance to chemotherapy, relapse, and metastasis. We have shown that a TSC-related protein, doublecortin- like kinase 1 (DCLK1) is induced in hepatotoxicity-induced liver injury, chronic hepatitis, cirrhosis, and HCC whereas a normal liver lacks DCLK1 expression. The elevated DCLK1 level promotes hepatoma cell migration, cell cycle progression, and HCC-like tumor growth. Our central hypothesis is that activation of DCLK1-expressing cells contributes to the development of hepatic neoplasia and, ultimately, HCC. Targeting the DCLK1-expressing subpopulation and DCLK1 regulated signaling will reduce the burden of cancer-related deaths. The proposed investigations rely on the use of primary human hepatocytes derived from normal and patient donors. We will determine the mechanism(s) which promote DCLK1-expressing human hepatocytes to acquire tumor characteristics. We will use cell culture and a unique mouse model with humanized/chimeric liver to test the hypothesis. We will also develop HCC patients-derived tumor xenografts to evaluate the impacts of targeting DCLK1 in HCC. Taken together, these studies will increase our understanding of the mechanism(s) that regulate hepatic neoplasia and will potentially validate DCLK1 as a new therapeutic target in HCC. These studies, if successful, will have a major impact on the field of cancer and veterans’ health because DCLK1 also contributes to the tumor growth in pancreas, intestine, and colon. !

肝细胞癌 (HCC) 是肝癌的一种主要形式，是导致肝癌的第二常见原因。其预后较差，5年生存率低于15%。 VA 医疗保健使用者中肝硬化和 HCC 的全国患病率和死亡率在过去十年中，HCC 发病率预计增加 2.5 至 3 倍。美国退伍军人群体中与肝癌相关的死亡人数仍然令人震惊。肝硬化、脂肪肝和接触肝毒素是肝癌发生的主要危险因素。患有糖尿病和肥胖的 HCV 携带者患 HCC 的风险显着增加，因此，HCC 是一种主要的疾病。 FDA 批准的单一 HCC 治疗方法，索拉非尼只能将生存期延长约 3 个月，治疗性手术选择包括肝脏手术。然而，由于晚期，很少有患者适合接受手术。 HCC 的诊断是阻碍有效治疗方法开发的主要障碍之一。是由于 HCC 中可能存在肿瘤干细胞 (TSC)。 TSC 群体中一小部分（1% 至 2%）被认为对耐药性负有责任我们已经证明 TSC 相关蛋白，双皮质素 - 类似激酶 1 (DCLK1) 在肝毒性引起的肝损伤、慢性肝炎、肝硬化和 HCC 而正常肝脏缺乏 DCLK1 表达，DCLK1 水平升高会促进肝癌。我们的中心假设是，细胞迁移、细胞周期进展和 HCC 样肿瘤生长。 DCLK1 表达细胞的激活有助于肝肿瘤的发展，最终，针对表达 DCLK1 的亚群和 DCLK1 调节的信号传导将成为 HCC 的目标。减少癌症相关死亡的负担拟议的调查依赖于初级研究的使用。我们将确定来自正常和患者捐赠者的人类肝细胞的机制。我们将使用它促进表达 DCLK1 的人肝细胞获得肿瘤特征。我们将通过细胞培养和具有人源化/嵌合肝脏的独特小鼠模型来检验这一假设。还开发了 HCC 患者来源的肿瘤异种移植物，以评估靶向 DCLK1 的影响总而言之，这些研究将增加我们对 HCC 机制的理解。调节肝肿瘤，并有可能验证 DCLK1 作为 HCC 的新治疗靶点。这些研究如果成功，将对癌症和退伍军人健康领域产生重大影响因为 DCLK1 也有助于胰腺、肠和结肠中的肿瘤生长。！