Novel prostate cancer oncogenes identified by transposon mutagenesis

描述（由申请人提供）：我们进行了两个物种的试点筛选，以发现新的致癌基因和肿瘤抑制基因，可以驱动小鼠和人类前列腺癌的启动和/或进展。初步筛选在小鼠中利用基于转座子的插入诱变来模拟前列腺癌的遗传异质性，并对新的癌基因和肿瘤抑制基因进行全基因组筛选。二次筛选使用人类前列腺癌患者样本，通过检查人类前列腺癌中表达改变的基因的人类直系同源物来验证新候选癌症基因的相关性。该筛选鉴定了几个新的候选前列腺癌癌基因和肿瘤抑制基因。在小鼠筛选中鉴定的首批基因之一PDE 4D也在人类前列腺癌患者样本中过度表达。此外，PDE 4D的敲除可以减少体外和体内人前列腺癌细胞的增殖。该提案将调查新的候选前列腺癌癌基因和肿瘤抑制基因，已确定在我们的屏幕上，特别强调评估PDE 4D作为候选前列腺癌癌基因和潜在的药物靶点在前列腺癌中的作用。该提案的目的1和2中的实验将模拟正常前列腺中的PDE 4D过表达，并研究PDE 4D在前列腺中的作用机制。目标3中的实验将测试NVP-ABE 171（一种PDE 4D选择性小分子抑制剂）作为临床前模型背景下的潜在抗前列腺癌药物。目的4中的实验将评估在我们的初步研究中鉴定的PDE 4D和其他新的候选前列腺癌基因的表达，以评估与人类前列腺癌的不同病理等级相关的表达变化和/或预测长期患者结果的表达。总的来说，这些研究将使人们更好地了解推动前列腺癌进展的遗传多样性途径，并确定PDE 4D作为前列腺癌新药靶点的适用性。 公共卫生相关性：目前，对人类前列腺癌之间的表型和遗传异质性的理解不足，无法根据个体患者的需要定制前列腺癌治疗。该项目将导致更好地了解在不同前列腺肿瘤中驱动前列腺癌进展的遗传多样性途径。这将成为开发新的诊断测试的重要一步，可以预测个体前列腺癌患者的最佳治疗方案。该项目还将评估NVP-ABE 171作为一种潜在的前列腺癌新疗法。

DESCRIPTION (provided by applicant): We have conducted a two-species pilot screen to discover new oncogenes and tumor suppressor genes that can drive prostate cancer initiation and/or progression in mice and humans. The primary screen utilized transposon-based insertional mutagenesis in mice to model genetic heterogeneity in prostate cancer and conduct a genome-wide screen for new oncogenes and tumor suppressor genes. The secondary screen used human prostate cancer patient samples to validate the relevance of novel candidate cancer genes by examining the human orthologs of the genes for altered expression in human prostate cancers. This screen identified several novel candidate prostate cancer oncogenes and tumor suppressor genes. One of the first genes identified in the mouse screen, PDE4D, was also over-expressed in human prostate cancer patient samples. Furthermore, knockdown of PDE4D reduced the proliferation of human prostate cancer cells in vitro and in vivo. This proposal will investigate the novel candidate prostate cancer oncogenes and tumor suppressor genes that have been identified in our screen with a particular emphasis on evaluating the roles of PDE4D as a candidate prostate cancer oncogene and potential drug target in prostate cancer. Experiments in Aims 1 and 2 of the proposal will model PDE4D over-expression in the normal prostate and investigate the mechanism of PDE4D action in the prostate. Experiments in Aim 3 will test NVP- ABE171, a PDE4D-selective small molecule inhibitor, as a potential anti-prostate cancer drug in the context of pre-clinical models. Experiments in Aim 4 will evaluate the expression of PDE4D and other novel candidate prostate cancer genes identified in our preliminary studies for expression changes associated with different pathologic grades of human prostate cancer and/or expression that is predictive of long-term patient outcomes. Collectively, these studies will lead to a better understanding of the genetically diverse pathways that drive prostate cancer progression, and they will determine the suitability of PDE4D as a new drug target in prostate cancer. PUBLIC HEALTH RELEVANCE: Currently, there is insufficient understanding of the phenotypic and genetic heterogeneity among human prostate cancers to tailor prostate cancer treatment to the needs of individual patients. This project will lead to a better understanding of the genetically diverse pathways that drive prostate cancer progression in different prostate tumors. This will constitute an important step toward developing new diagnostic tests that can predict the best treatment option for individual prostate cancer patients. This project will also evaluate NVP-ABE171 as one potential new treatment for prostate cancer.