An integrative approach to cancer gene discovery in hepatocellular carcinoma

我们的应用程序解决了肝细胞癌的主要医学问题，这是第三大 导致全球癌症死亡的原因。与其他主要致命性癌症相比，这种癌症研究不足 迫切需要新的治疗方法。目前唯一能延长存活期的治疗方法是移植 以及手术切除/消融，这些只对少数患者有效。此外， 肝细胞癌是一种天然的化疗耐药，目前还没有发现可以提高生存率的药物。 为了开发更有效的治疗方法，我们需要更好地了解潜在的分子。 驱动肝细胞癌发生的改变，并彻底测试它们的功能意义。为此， 我们组建了一个在癌症靶点领域有着长期合作历史的研究团队 发现和验证新的癌基因和肿瘤抑制基因 在肝细胞癌。我们的方法集成了一系列强大的技术，都是在冷泉港开发的 实验室，识别和优先处理肝细胞癌的基因组改变，并提供深入研究的工具 它们与癌症的生物学相关性。潜在的癌基因和肿瘤抑制基因由一种 敏感和高分辨率数组方法，然后按跨物种对它们可能的相关性进行优先排序 比较和表达研究。高优先级的候选人使用高度的 易于处理的小鼠肝癌模型，允许快速分析基因和基因组合。验证 开发新的RNA干扰技术来有条件地稳定地沉默基因 在体外和体内表达。我们提供了一系列广泛的初步结果来验证这一点 方法，包括证明人类和小鼠肝癌有共同的遗传损伤，以及 高通量小鼠肝癌模型的建立。最后，我们使用这种方法来识别和 验证clAP1是一种新的肝癌相关癌基因。我们的结果将产生对分子的新见解 肝细胞癌发生的基础，并应确定这种高度致命的关键治疗靶点 癌症。

Our application addresses the major medical problem of hepatocellular carcinoma, the third leading cause of cancer death worldwide. This cancer is understudied compared to other major lethal cancers and is in desperate need of new therapies. The only current treatments that prolong survival are transplantation and surgical resection/ablation, and these are effective only in a minority of patients. Moreover, hepatocellular carcinoma is inherently chemoresistant and no drugs have been shown to improve survival. To develop more effective therapeutics we need a better understanding of the underlying molecular alterations that drive HCC development and thoroughly test their functional significance. Towards this end, we have assembled a research team with a long history of collaboration in the area of cancer target discovery and validation to identify and characterize new oncogenes and tumor suppressor genes involved in HCC. Our approach integrates a series of powerful technologies, all developed at Cold Spring Harbor Laboratory, that both identify and prioritize genomic alterations in HCC, and provide tools to thoroughly study their biological relevance to cancer. Potential oncogenes and tumor suppressor genes are identified by a sensitive and high-resolution array method and then prioritized for their likely relevance by cross-species comparison and expression studies. High priority candidates are tested and validated using a highly tractable mouse model of HCC that allows for rapid analysis of genes and gene combinations. Validation approaches exploit new RNA interference technology to both conditionally and stably silence gene expression in vitro and in vivo. We provide an extensive series of preliminary results that have validated this approach, including demonstration that human and murine HCCs have common genetic lesions and the development of a high throughput model of murine HCC. Finally, we have used this approach to identify and validate clAP1 as a new oncogene relevant to HCC. Our results will produce new insights into the molecular basis of hepatocellular carcinogenesis and should identify key therapeutic targets for this highly lethal cancer.