Genetics pathways in intra-hepatic cholangiocarcinoma

描述(申请人提供)：肝内胆管细胞癌(IHCC)是一种发病率上升且预后不佳的原发性肝癌，近几十年来仅有轻微改善。其他类型的成人恶性肿瘤，通常通过其癌症的特定特征，如基因变化，可以识别出亚组患者，并受益于针对该疾病亚型使用的量身定制的治疗方法。这样的策略还没有被开发出来用于胆管癌。此外，对这种癌症潜在的遗传和分子方面的了解很少，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)开发了一种基于人类疾病的新的小鼠模型。我们的遗传学研究建立了两种截然不同的疾病亚集，新模型显示了人类疾病的许多特征。此外，该模型表明，在人类体内观察到的肝脏早期变化可能是导致IHCC的前驱步骤。我们还利用这一模型成功地测试了一种新的治疗方法，该方法使用一种著名的药物氯喹来治疗这些肿瘤的一部分。基于这些发现，我们将使用人类组织和动物模型来回答1)这种肿瘤是从肝脏的哪里产生的，最早的基因变化是什么，2)其他基因变化如何影响肿瘤的行为，3)肿瘤亚型如何影响药物氯喹阻止其生长的能力。考虑到疾病的严重性和这种药物立即可用于临床，这些研究可能会立即对患者产生积极影响。 得了这种病。此外，这项研究产生的许多新的疾病模型和试剂将使其他专注于这种疾病的研究取得进展。

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.