Novel Mouse Models to define Genetic Drivers of Aggressive Prostate Cancer

 描述（由申请人提供）：前列腺癌（PCa）知识的一个基本空白是如何区分惰性和侵袭性疾病。此外，将惰性PCa转换为侵袭性表型的遗传事件尚未得到很好的理解。我们拟定的研究将利用PI生成的两种最先进的PCa基因工程小鼠模型（GEMM）来解决这些知识空白。小鼠前列腺上皮细胞专有的Myc癌基因的表达导致惰性器官局限性PCa。我们将Myc转基因小鼠模型与其他模型相结合，以建立PCa的新型GEMM，从而进行基因候选和基因发现方法，以描绘侵袭性PCa进展的遗传驱动因素。具体而言，目标1将确定视网膜母细胞瘤蛋白（Rb）是否是PCa转移的抑制因子。具体目标2将利用睡美人诱变筛选来鉴定PCa转移的新的候选遗传驱动因素。最终，这些新的和最先进的小鼠模型允许研究前列腺特异性分子事件。我们的主要目标是表征我们的GEMM，以发现驱动侵略性PCa的基因开关。总的来说，我们提出的研究将显著影响PCa研究以及如何对患者进行临床评估以确定惰性和侵袭性疾病的分层。此外，通过完成这些研究，我们将继续实现我们的长期目标，即识别和验证可能最终用于治疗晚期PCa患者的新治疗途径/靶点，以及识别侵袭性PCa表型的PCa血清可用生物标志物。

 DESCRIPTION (provided by applicant): A fundamental gap in knowledge in prostate cancer (PCa) is how to distinguish indolent from aggressive disease. Further, genetic events that switch an indolent PCa to an aggressive phenotype are not well understood. Our proposed investigations will utilize two state-of-the-art genetically engineered mouse models (GEMMs) of PCa generated by the PI to address these gaps in knowledge. Expression of the Myc oncogene exclusive to mouse prostate epithelium results in indolent organ confined PCa. We have combined the Myc transgenic mouse model with additional models to establish novel GEMMs of PCa to perform a gene candidate and gene discovery approach to delineate genetic drivers of aggressive PCa progression. Specifically, aim 1 will determine if the retinoblastoma protein (Rb) is a suppressor of PCa metastasis. Specific aim 2 will utilize a sleeping beauty mutagenesis screen to identify novel candidate genetic drivers of PCa metastasis. Ultimately, these novel and state-of-the-art mouse models allow for prostate specific molecular events to be investigated. Our principle objective is to characterize our GEMMs to discover genetic switches which drive aggressive PCa. Overall, our proposed studies will significantly impact PCa research and how patients are clinically assessed to determine stratification of indolent from aggressive disease. In addition, through completing these studies, we will continue to achieve our longer term goals which are to identify and validate new therapeutic pathways/targets that may ultimately be used to treat patients with advanced PCa, and serum available biomarkers of PCa that identify aggressive PCa phenotypes.