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肿瘤小鼠模型领域的领导者。我们有 开发了一套基因工程小鼠模型，可证明代表人类 神经胶质瘤和其他类型的肿瘤。这些模型已被用于告知临床药物的治疗选择， 这使我们能够提出这些模型是测试潜在重大改进的合适测试平台 如何治疗这些疾病。我们有三个项目。1)我们正在理解具体的 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 系统已在此用于显示胚胎剪接变体在成体组织中强制表达 导致广泛的癌症形成。在这个项目中，我们将研究这种肿瘤发生的机制。 剪接变体并确定其是否可以成为良好诊断或治疗靶点。2)我们现在使用 为神经胶质瘤开发的建模系统，以解决基因融合驱动的罕见肿瘤的生物学问题。在这 因此，我们建议了解罕见肿瘤中YAP 1基因融合的致癌机制 室管膜瘤、汗孔癌和侵袭性脑膜瘤（所有这些我们都有YAP 1基因融合驱动 模型目前）。3)并且，我们将使用这些小鼠模型来研究治疗反应， 这些融合驱动肿瘤的治疗策略，包括鉴定FDA批准的药物， 干预基因融合作用的下游。

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.