Novel prostate cancer oncogenes identified by transposon mutagenesis

通过转座子诱变鉴定出新的前列腺癌癌基因

• 批准号: 8034799
• 负责人: Paul C Marker
• 金额: $ 29.16万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-03-01 至 2014-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8034799
• 关键词: Adenocarcinoma; Antibodies; Antineoplastic Agents; Cancer Patient; Collection; Complementary DNA; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Diagnostic tests; Drug Delivery Systems; Epithelial Cells; Genes; Genetic; Genetic Heterogeneity; Genetic Screening; Genomics; Growth; Histology; Human; Immunofluorescence Immunologic; In Situ Hybridization; In Vitro; Individual; Injection of therapeutic agent; Insertional Mutagenesis; Laboratories; Lead; Lesion; Location; Malignant neoplasm of prostate; Messenger RNA; Modeling; Molecular; Mus; Mutagenesis; Mutate; Neoplasm Metastasis; Nuclear; Oncogenes; Orthologous Gene; Outcome; PC3 cell line; Pathologic; Pathology; Pathway interactions; Patients; Phenotype; Pre-Clinical Model; Prostate; Prostatic; Prostatic Epithelium; Prostatic Neoplasms; Protein Isoforms; Rattus; Relative (related person); Reverse Transcriptase Polymerase Chain Reaction; Role; Sampling; Site; Staining method; Stains; Testing; Time; Tissue Microarray; Transgenic Mice; Transgenic Organisms; Tumor Suppressor Genes; Tumor Suppressor Proteins; Xenograft procedure; base; cancer cell; cancer gene expression; cancer initiation; cancer therapy; follow-up; genome wide association study; human tissue; in vivo; inhibitor/antagonist; mRNA Expression; novel; novel diagnostics; prevent; probasin; promoter; protein expression; public health relevance; research study; small hairpin RNA; small molecule; tumor progression

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.

描述（由申请人提供）：我们进行了两个物种的试点筛选，以发现可以驱动小鼠和人类前列腺癌发生和/或进展的新癌基因和肿瘤抑制基因。初步筛选利用小鼠中基于转座子的插入诱变来模拟前列腺癌的遗传异质性，并对新的癌基因和抑癌基因进行全基因组筛选。第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基因的人类直系同源物的表达改变来验证新候选癌症基因的相关性。该筛选鉴定了几种新的候选前列腺癌癌基因和肿瘤抑制基因。 PDE4D 是小鼠筛选中最早发现的基因之一，它也在人类前列腺癌患者样本中过度表达。此外，PDE4D 的敲低可减少体外和体内人类前列腺癌细胞的增殖。该提案将研究我们筛选中已鉴定的新型候选前列腺癌癌基因和肿瘤抑制基因，特别强调评估 PDE4D 作为候选前列腺癌癌基因和前列腺癌潜在药物靶点的作用。该提案的目标 1 和 2 的实验将模拟正常前列腺中 PDE4D 的过度表达，并研究 PDE4D 在前列腺中的作用机制。目标 3 中的实验将测试 NVP-ABE171（一种 PDE4D 选择性小分子抑制剂）作为临床前模型中潜在的抗前列腺癌药物。目标 4 中的实验将评估 PDE4D 和我们初步研究中确定的其他新候选前列腺癌基因的表达，以了解与人类前列腺癌不同病理级别相关的表达变化和/或可预测患者长期结果的表达。总的来说，这些研究将有助于更好地了解驱动前列腺癌进展的遗传多样性途径，并将确定 PDE4D 作为前列腺癌新药物靶点的适用性。 公共健康相关性：目前，对人类前列腺癌的表型和遗传异质性了解不足，无法根据个体患者的需求调整前列腺癌治疗。该项目将有助于更好地了解不同前列腺肿瘤中驱动前列腺癌进展的遗传多样性途径。这将是开发新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选择。该项目还将评估 NVP-ABE171 作为前列腺癌的一种潜在新疗法。