The role and mechanism of alternative RNA splice variants and gene fusions as drivers of cancer

摘要 在过去的15年里，我的实验室一直是脑瘤小鼠模型领域的领先者。我们有 开发了一套明显代表人类的基因工程小鼠模型 胶质瘤和其他肿瘤类型。这些模型已经被用于为临床药物的治疗选择提供信息， 这使我们现在能够提出这些模型是测试潜在主要改进的合适试验台 这些疾病是如何治疗的。我们有三个项目。1)我们正在理解特定的核心作用 TrkB的剪接变体在胚胎发育和全身肿瘤发生中的作用。RCAS建模 该系统已被用来显示胚胎剪接变体在成人组织中的强制表达 会导致广泛的癌症形成。在这个项目中，我们将研究其致癌机制。 剪接变异体，并确定它是否可以作为良好的诊断或治疗靶点。2)我们现在使用 为胶质瘤开发的建模系统，以解决由基因融合驱动的罕见肿瘤的生物学问题。在这 我们建议了解罕见肿瘤中YAP1基因融合的致癌机制 室管膜瘤、前列腺癌和侵袭性脑膜瘤(我们对所有这些都有YAP1基因融合驱动 当前型号)。3)并且，我们将使用这些小鼠模型来研究治疗反应和识别 这些融合驱动的肿瘤的治疗策略包括识别FDA批准的药物 干预下游基因融合的作用。

Abstract My lab has been the leader in the field of mouse modeling for brain tumors over the past 15 years. We have developed a suite of genetically engineered mouse models that are demonstrably representative of human gliomas and other tumor types. These models have been used to inform treatment options for clinical agents, and this now enables us to propose these models are suitable testbeds for testing potential major improvements to how these diseases are treated. We have three projects. 1) We are understanding the central role of specific splice variants of TrkB in embryonic development and oncogenesis throughout the body. The RCAS modeling system has been used here to show that forced expression of the embryonic splice variant in adult tissues leads to cancer formation broadly. In this project we will investigate the mechanisms of oncogenesis for this splice variant and determine if it could be a good diagnostic or therapeutic target. 2) We are now using the modeling system developed for glioma to address the biology of rare tumors driven by gene fusions. In this grant we propose to understand the mechanisms of oncogenesis for YAP1 gene fusions in the rare tumors ependymoma, porocarcinoma and aggressive meningioma (all for which we have YAP1 gene fusion driven models currently). 3) And, we will use these mouse models to study therapeutic response and identify therapeutic strategies for these fusion driven tumors including identification of FDA approved drugs that would intervene downstream of the action of the gene fusion.