Novel prostate cancer oncogenes identified by transposon mutagenesis

描述（由申请人提供）：我们已经进行了一个两种先导筛选，以发现新的致癌基因和肿瘤抑制基因，这些基因可以驱动小鼠和人类前列腺癌的发生和/或进展。初级筛选在小鼠中利用基于转座子的插入突变来模拟前列腺癌的遗传异质性，并对新的致癌基因和肿瘤抑制基因进行全基因组筛选。二级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同源物来验证新的候选癌症基因的相关性。该筛选发现了几个新的候选前列腺癌癌基因和肿瘤抑制基因。在小鼠筛选中发现的首批基因之一PDE4D在人类前列腺癌患者样本中也过表达。此外，PDE4D基因的敲低降低了人前列腺癌细胞的体外和体内增殖。本提案将研究在我们的筛选中发现的新的候选前列腺癌癌基因和肿瘤抑制基因，特别强调评估PDE4D作为前列腺癌候选癌基因和前列腺癌潜在药物靶点的作用。本文目的1和目的2的实验将模拟PDE4D在正常前列腺中的过表达，并探讨PDE4D在前列腺中的作用机制。Aim 3的实验将在临床前模型的背景下测试pde4d选择性小分子抑制剂NVP- ABE171作为潜在的抗前列腺癌药物。Aim 4的实验将评估PDE4D和我们在初步研究中发现的其他新的前列腺癌候选基因的表达变化与不同病理级别的人类前列腺癌和/或预测患者长期预后的表达。总的来说，这些研究将有助于更好地理解驱动前列腺癌进展的遗传多样性途径，并将确定PDE4D作为前列腺癌新药靶点的适用性。

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.