ALTERED GROWTH FACTOR PATHWAYS IN BILIARY CANCER

描述(申请人提供)：肝内胆管细胞癌(CHC)是一种高度致命的癌症，起源于肝脏的胆管上皮(胆管细胞)，可能来自与肝脏胆管相关的“干细胞”。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上的挑战，因为死亡率仍然很高，CHC的细胞和分子发病机制仍然不清楚，到目前为止还没有有效的化疗策略来治疗这种毁灭性的癌症。促进我们对CHC发生发展的关键分子机制的理解的一个主要限制是无法实现培养的胆管细胞的肿瘤性转化。在之前的资助期间，我们提供的数据支持结构性激活的ERBB-2的过度表达和COX-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个新的大鼠胆管上皮细胞系的肿瘤转化，在逆转录病毒感染突变的大鼠erbB-2癌基因，并确定COX-2在恶性转化中上调。当将这些细胞移植到同基因大鼠体内时，这些细胞产生了CHC。为了扩展这些令人兴奋的结果，我们现在建议(1)进一步建立和表征新的基于ErbB信号调节失调的、按不同阶段定义的转基因和自发转化的大鼠胆管细胞体外模型；(2)确定与上调的COX-2相关的ErbB-2信号的异常是否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功能；(3)检测同源盒转录因子CDX1是否通过体外转化的胆管细胞调节粘蛋白腺体的组织发生；(4)评价目前处于临床试验中的ErbB1/ErbB-2双酪氨酸激酶抑制剂GW572016在体内外对恶性胆管细胞的治疗作用。从这些研究中，我们期待着强大的新的胆管细胞恶性转化的实验模型和CHC在新的临床前检测中的选择性靶向治疗。

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.