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，肝细胞癌是全球癌症死亡的第三大原因。与其他主要致命癌症相比，这种癌症的研究不足，迫切需要新的治疗方法。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，这些方法仅对少数患者有效。此外，肝细胞癌是固有的化疗耐药，没有药物已被证明可以提高生存率。为了开发更有效的治疗方法，我们需要更好地了解驱动HCC发展的潜在分子改变，并彻底测试其功能意义。为此，我们组建了一个在癌症靶点发现和验证领域具有悠久合作历史的研究团队，以识别和表征HCC中涉及的新癌基因和肿瘤抑制基因。我们的方法整合了一系列强大的技术，所有这些技术都是在冷泉港实验室开发的，这些技术可以识别和优先考虑HCC中的基因组改变，并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灵敏和高分辨率的阵列方法鉴定，然后通过跨物种比较和表达研究优先考虑它们可能的相关性。高优先级的候选人进行测试和验证，使用一个高度听话的肝癌小鼠模型，允许快速分析基因和基因组合。验证方法利用新的RNA干扰技术在体外和体内有条件地和稳定地沉默基因表达。我们提供了一系列广泛的初步结果，验证了这种方法，包括证明人类和小鼠HCC具有共同的遗传病变和小鼠HCC的高通量模型的发展。最后，我们使用这种方法来确定和验证cIAP 1作为一个新的癌基因相关的肝癌。我们的研究结果将对肝细胞癌发生的分子基础产生新的见解，并应确定这种高致死性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.