An integrative approach to cancer gene discovery in hepatocellular carcinoma

描述(由申请人提供)：我们的申请解决了肝细胞癌的主要医学问题，这是全球第三大癌症死亡原因。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和外科切除/消融，这些方法只对少数患者有效。此外，肝细胞癌具有天然的化疗耐药性，目前还没有发现可以提高存活率的药物。为了开发更有效的治疗方法，我们需要更好地了解推动肝癌发生的潜在分子变化，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发现和验证领域具有长期合作历史的研究团队，以识别和表征与肝癌相关的新癌基因和肿瘤抑制基因。我们的方法集成了一系列强大的技术，这些技术都是在冷泉港实验室开发的，既可以识别并优先处理肝细胞癌中的基因组变化，又可以提供工具来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通过敏感和高分辨率的阵列方法识别，然后通过跨物种比较和表达研究来确定它们可能的相关性。使用高度易处理的肝细胞癌小鼠模型对高优先级候选进行测试和验证，该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体外和体内的基因表达。我们提供了一系列验证这一方法的初步结果，包括证明人类和小鼠肝癌具有共同的遗传损伤，以及建立高通量的小鼠肝癌模型。最后，我们用这种方法鉴定并验证了clAP1是一个与肝癌相关的新的癌基因。我们的结果将对肝细胞癌发生的分子基础产生新的见解，并应该确定这种高度致命的癌症的关键治疗靶点。

DESCRIPTION (provided by applicant): 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.