Genetics pathways in intra-hepatic cholangiocarcinoma

描述（由申请人提供）：肝内胆管癌（IHCC）是一种原发性肝癌，发病率上升，预后差，近几十年来仅略有改善。其他类型的成人恶性肿瘤，通常可以通过其癌症的特定特征（如遗传变化）来确定患者的亚组，这些肿瘤受益于针对该疾病亚型的量身定制的治疗方法。目前还没有针对胆管癌的治疗策略。此外，对这种癌症类型的遗传和分子基础了解不足，限制了早期发现和预防的方法。研究一直受到相对较少的人类肿瘤细胞系和动物模型系统的阻碍。为了应对这些障碍，我们a)对这种疾病的遗传学进行了广泛的研究，b)基于人类疾病开发了一种新的小鼠模型。我们的遗传研究建立了两种不同的疾病亚群，新模型显示了人类疾病的许多特征。此外，该模型表明，在人类中观察到的肝脏早期变化可能是导致IHCC的前兆步骤。我们也用这个模型成功地测试了一种新的治疗方法，使用一种众所周知的药物，氯喹，来治疗这些肿瘤的一部分。基于这些发现，我们将使用人体组织和动物模型来回答1)这种肿瘤从肝脏的哪里出现以及最早的遗传变化是什么，2)其他遗传变化如何影响肿瘤行为，以及3)肿瘤亚型如何影响药物氯喹阻止其生长的能力。鉴于疾病的严重程度和这种药物在临床使用的即时可用性，这些研究可能会对患者产生直接的积极影响

DESCRIPTION (provided by applicant): Intra-hepatic cholangiocarcinoma (IHCC) is a primary cancer of the liver with a rising incidence and poor outcomes that have improved only marginally in recent decades. Other types of adult malignancies where sub-groups of patients can be identified, often by particular feature of their cancer such as a genetic change, have benefitted from tailored therapies in which treatment is used specific to that disease subtype. Such strategies have not been developed for cholangiocarcinoma. Moreover, there is a poor understanding of genetic and molecular underlying this cancer type, limiting approaches toward early detection and prevention. Research has been hampered by a relatively few human tumor cell lines and animal model systems. In response to these roadblocks we a) conducted extensive work on the genetics of this disease and b) developed a new mouse model based on the human disease. Our genetic studies established two distinct subsets of disease and the new model displays many characteristic features of the human disease. Furthermore, the model suggests that early changes in the liver that are observed in humans may be precursor steps that lead to IHCC. We have also used this model to successfully test a novel treatment approach using a well-known drug, chloroquine, for a subset of these tumors. Based on these findings, we will use human tissues and animal models to answer 1) where in the liver does this tumor emerge from and what are the earliest genetic changes, 2) how do other genetic changes influence tumor behavior, and 3) how does the tumor subtype affect the ability of the drug chloroquine to stop its growth. Given the severity of the disease and the immediate availability of this drug for clinical use these studies could lead to an immediate positive effect for patients with the disease. Moreover, many new models of disease and reagents produced by this study will enable others focused on research in this disease to make forward progress.