An integrative approach to cancer gene discovery in hepatocellular carcinoma

我们的应用解决了肝细胞癌的主要医学问题，这是第三大主要的医学问题。 全球癌症死亡原因。与其他主要致命癌症相比，这种癌症的研究不足， 急需新的疗法目前唯一能延长生存期的治疗方法是移植 和手术切除/消融，这些仅对少数患者有效。此外，委员会认为， 肝细胞癌具有固有的化学抗性，并且没有药物显示出改善存活率。 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机制， 这些改变驱动HCC的发展，并彻底测试其功能意义。为此， 我们组建了一个在癌症靶点领域有着悠久合作历史的研究团队， 发现和验证以鉴定和表征涉及的新癌基因和肿瘤抑制基因 在HCC。我们的方法集成了一系列强大的技术，所有这些技术都是在冷泉港开发的 实验室，既确定和优先考虑HCC中的基因组改变，并提供工具，以彻底研究 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是通过 敏感和高分辨率的阵列方法，然后优先考虑它们可能的相关性， 比较和表达研究。高优先级的候选人将使用 一种易于处理的HCC小鼠模型，允许快速分析基因和基因组合。验证 方法利用新的RNA干扰技术来有条件地和稳定地沉默基因 体外和体内表达。我们提供了一系列广泛的初步结果，证实了这一点 方法，包括证明人类和小鼠HCC具有共同的遗传病变， 小鼠HCC的高通量模型的开发。最后，我们使用这种方法来识别和 证实cIAP 1是一个与HCC相关的新癌基因。我们的研究结果将产生新的见解， 肝细胞癌发生的基础，并应确定这种高致死性的关键治疗靶点。 癌

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.