Mechanisms by which Oncogene Inactivation Elicits Tumor Cell Death

描述（由申请方提供）：癌基因的靶向失活可引起强烈的细胞死亡，表明肿瘤可对突变的原癌基因“上瘾”。了解肿瘤对癌基因上瘾的原因并预测其发生的时间，将对癌症治疗的发展产生深远的影响。这将为选择分子靶点提供更合理的基础，识别潜在的新的非癌基因靶点，促进肿瘤的治疗， 筛选潜在的药物，并提供选择最有可能受益的患者的策略 从特定的靶向治疗。为了研究癌基因成瘾，我们利用泰特系统建立了条件性转基因小鼠模型。我们已经创建了几种条件癌基因（MYC，RAS，BCL-2，BCR-ABL），以创建不同癌症的转基因小鼠模型，包括：T-急性淋巴细胞白血病（T-ALL），急性髓性白血病（AML），成骨肉瘤（OS）和肝细胞癌（HCC）。我们发现癌基因失活的结果依赖于细胞和遗传背景。癌基因成瘾涉及肿瘤细胞内在和宿主依赖性程序，包括自我更新的永久丧失或诱导细胞衰老和宿主依赖性程序。我们现在能够更普遍地定义这些机制如何促进癌基因失活诱导细胞死亡。我们的假设是，癌基因成瘾可以模拟为细胞死亡和生存信号之间的差异反应。我们将定义关键的Lynch pin基因产物和途径。我们的方法将是进行定量原位分析，使用活体显微镜和免疫组化结合比较蛋白质组学和基因组学分析。我们将在不同的遗传背景下使用不同的条件癌基因和癌症类型进行这些研究，然后使用数学建模和计算生物学方法来揭示常见的关键基因，并定义它们在癌基因成瘾中的机制作用。 公共卫生相关性：癌基因失活可引起癌基因成瘾现象。了解癌基因失活诱导细胞死亡的机制将对癌症治疗的发展产生广泛的影响。

DESCRIPTION (provided by applicant): The targeted inactivation of oncogene can elicit robust cell death suggesting that tumors can be "addicted" to a mutated proto-oncogene. Understanding why and predicting when tumors are addicted to oncogenes would have protean implications for the development of therapies for cancer. This would enable a more rational basis for choosing molecular targets, identify potentially new non-oncogene targets, facilitate the screening for potential agents and provide a strategy for selecting patients most likely to benefit from specific targeted therapeutic. To study oncogene addiction, we have used the Tet system to develop conditional transgenic mouse models. We have created several conditional oncogenes (MYC, RAS, BCL-2, BCR-ABL), to create transgenic mouse models of different cancers including: T-acute lymphoblastic leukemia (T-ALL), acute myeloid leukemia (AML), osteogenic sarcoma (OS), and hepatocellular carcinoma (HCC). We have found that the consequences of oncogene inactivation are dependent upon both cellular and genetic context. Oncogene addiction involves tumor cell intrinsic and host dependent programs including the permanent loss of self- renewal or induction of cellular senescence and host-dependent programs. We are in the position to now define more generally how these mechanisms contribute oncogene inactivation induced cel death. Our hypothesis is that oncogene addiction can be modeled as a differential response between cel death and survival signaling. We will define key lynch pin gene products and pathways. Our approach will be to perform a quantitative in situ analysis using intravital microscopy and imunohistochemistry combined with a comparative proteomic and genomic analysis. We will perform these studies using different conditional oncogenes and types of cancer in different genetic contexts and then use mathematical modeling and computational biological approaches to reveal the common lynch pin genes and define their mechanistic role in oncogene addiction. PUBLIC HEALTH RELEVANCE: Oncogene inactivation can elicit the phenomenon of oncogene addiction. Understanding the mechanism by which oncogene inactivation induces cell death would have broad implications for the development of therapies for cancer.