ALTERED GROWTH FACTOR PATHWAYS IN BILIARY CANCER

胆道癌中生长因子途径的改变

• 批准号: 6865103
• 负责人: ALPHONSE E SIRICA
• 金额: $ 31.88万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-08 至 2010-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6865103
• 关键词: biliary tract; biliary tract neoplasm; biological signal transduction; disease /disorder model; histogenesis; kinase inhibitor; laboratory rat; molecular oncology; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; neoplastic transformation; oncoproteins; prostaglandin endoperoxide synthase; tissue /cell culture; transcription factor; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Intrahepatic cholangiocarcinoma (ChC) is a highly lethal cancer arising from biliary epithelium (cholangiocytes) of liver, possibly from "stem-like" cells associated with the hepatic biliary tract. Recent epidemiological studies have shown an increase in the worldwide incidence of ChC, including in the United States. However, ChC remains a clinical and biological challenge, since mortality rates continue to be very high, the cellular and molecular pathogenesis of ChC is still unclear, and there are to date no effective chemotherapeutic strategies for this devastating cancer. A major limitation to advancing our understanding of critical molecular mechanisms underlying the development of ChC has been the inability to achieve neoplastic transformation of cultured cholangiocytes. During the previous funding period, we have provided data supporting overexpression of constitutively activated ERBB-2 together with up-regulation of COX-2 as playing a potentially significant role in the molecular pathogenesis of ChC. We also very recently achieved neoplastic transformation of a novel rat biliary epithelial cell line following retroviral infection with the mutated rat erbB-2 oncogene, and determined COX-2 to be up-regulated in the malignant transformants. These cells gave rise to ChC when transplanted into syngeneic rats. In order to expand upon these exciting results, we now propose to (1) further establish and characterize novel in vitro models of genetically-mediated and spontaneous transformed rat cholangiocytes based on dysregulation of ErbB signaling and defined by discreet stages; (2) determine if aberrant ErbB-2 signaling linked to up-regulated COX-2 serves as a molecular switch for activating the angiogenic tumor cell phenotype as a function of malignant transformation of cholangiocytes; (3) test if the homeobox transcription factor CDX1 regulates mucin gland histogenesis by in vitro transformed cholangiocytes; and (4) assess the potential therapeutic effects of GW572016, a dual ErbB1/ErbB-2 tyrosine kinase inhibitor currently in clinical trials, against malignant cholangiocytes in vitro and in vivo. Powerful new experimental models of cholangiocyte malignant transformation and selective therapeutic targeting of ChC in novel preclinical assays are anticipated from these studies.

描述（由申请方提供）：肝内胆管细胞癌（ChC）是一种高致死性癌症，来源于肝脏的胆管上皮（胆管细胞），可能来源于与肝胆管相关的“干细胞样”细胞。最近的流行病学研究表明，包括美国在内的世界范围内ChC的发病率有所增加。然而，ChC仍然是一个临床和生物学挑战，因为死亡率仍然非常高，ChC的细胞和分子发病机制仍然不清楚，迄今为止还没有针对这种毁灭性癌症的有效化疗策略。一个主要的限制，以推进我们的理解的关键分子机制的发展ChC一直无法实现培养的胆管细胞的肿瘤转化。在之前的资助期间，我们提供的数据支持组成性激活ERBB-2的过度表达以及考克斯-2的上调在ChC的分子发病机制中发挥潜在的重要作用。我们最近还实现了一种新的大鼠胆管上皮细胞系的肿瘤转化逆转录病毒感染突变的大鼠erbB-2癌基因，并确定考克斯-2被上调的恶性转化。这些细胞移植到同系大鼠体内后产生ChC。为了扩展这些令人兴奋的结果，我们现在建议（1）进一步建立和表征基于ErbB信号转导失调和由离散阶段定义的遗传介导和自发转化的大鼠胆管细胞的新的体外模型;（2）确定异常ErbB-2信号传导是否与上调的考克斯-2相关，2作为激活血管生成肿瘤细胞表型的分子开关，作为胆管细胞恶性转化的函数;（3）通过体外转化的胆管细胞检测同源框转录因子CDX 1是否调节粘蛋白腺组织发生;（4）评价目前正在临床试验中的ErbB 1/ErbB-2酪氨酸激酶双重抑制剂GW 572016在体外和体内对恶性胆管细胞的潜在治疗作用。从这些研究中，我们可以预见到胆管细胞恶性转化的强大的新实验模型和ChC在新的临床前试验中的选择性治疗靶向。