Integration of Vascular Genomics and Proteomics for Diagnosis and Therapy of Canc

血管基因组学和蛋白质组学的整合在癌症诊断和治疗中的应用

• 批准号: 7905822
• 负责人: RENATA PASQUALINI
• 金额: $ 34.05万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-08 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7905822
• 关键词: Algorithms; Animal Model; Apoptosis; Automobile Driving; Bacteriophages; Bioinformatics; Biological; Biological Assay; Blood Vessels; Cells; Clinical; Companions; Data; Databases; Dependovirus; Development; Diagnosis; Diagnostic; Disease Progression; Effectiveness; Evaluation; Expressed Sequence Tags; Gene Expression; Gene Expression Profile; Genes; Genomics; Goals; Homing; Human Cell Line; Hybrids; Image; Imaging technology; In Vitro; Individual; Large-Scale Sequencing; Lead; Ligands; Malignant Neoplasms; Malignant neoplasm of prostate; Medicine; Modeling; Molecular Genetics; Monitor; Patients; Peptides; Pharmaceutical Preparations; Prostatic Neoplasms; Proteomics; Reporter; Reporter Genes; SAGE Library; Sampling; Suicide; System; Testing; Time; Transcript; Transgenes; Tumor Markers; United States Food and Drug Administration; Urine; Viral; Vision; base; cancer cell; cost; d(CH2)5(Tyr(Me)(2))AVP; design; genetic element; improved; in vivo; insight; molecular imaging; neoplastic cell; non-invasive monitor; particle; promoter; text searching; tool; tumor; tumor growth; vector

DESCRIPTION (provided by applicant): The integration of transcriptional profiling, cancer cells targeting and molecular-genetic imaging into a single platform would have many biological applications and the potential to improve the practice of medicine. We have designed and validated a new hybrid viral system composed of genetic elements from adeno-associated virus (AAV) and phage (termed AAVP). These ligand-directed particles enable targeted systemic delivery and imaging of transgene reporters. Experimental non-invasive monitoring of reporter trans-activation, may be followed ex-vivo and in vivo. Targeted molecular imaging would represent a major advance in the management of prostate cancer. The overall goal in this project is to combine the homing and tumor transducing capabilities of AAVP with cancer-specific promoters, as a way to develop improved tools for tumor monitoring based on the transcriptional activity of selected markers. These promoters will be identified by the large-scale evaluation of the transcriptome of cancer cells and tumor vasculature, using extensive searches in public databases, as well as by the construction and large-scale sequencing of SAGE libraries, using modern low-cost high throughput pyrosequencing approaches. The identified upregulated genes will be validated in two independent sample sets, and the promoters of confirmed upregulated transcripts will be identified, certified and cloned into AAVPs. With the definition of a reliable set of genes we expect to have comprehensive panel of tumor markers covering most of the gene expression variability seen in distinct patient tumor samples. The concept of establishing a panel of multiple markers is in line with the much heralded era of personalized medicine, and should launch, for the first time, a system for imaging temporally and spatially, in vivo, the transcriptional profile within tumors. The combination of a vector displaying peptides designed to target tumors, which also carries a suicide/reporter transgene (HSVtk) under the control of a tumor-specific promoter should enable transcriptional imaging and tumor growth suppression in a very specific fashion. The imaging and treatment possibilities of this vector reinforce the idea of drug-diagnostic co-development that, if preceded by an individual evaluation of gene expression (in the urine of patients with prostate cancer, for instance), could lead to a personalized diagnosis/treatment based on the up-regulated markers of an individual patient. This personalized imaging test merged with a companion drug comes together with the drug-diagnostic co-development concept recently put forward by the US Food and Drug Administration. Under this vision, the transcriptional imaging provided by a specific tumor gene will also trigger tumor apoptosis, allowing imaging as well as treatment and monitoring of disease progression. Our Specific Aims are: (i) To identify and to validate transcripts upregulated in prostate cancer using large scale transcriptome analysis. (ii) To combine ligand-directed targeting of AAVP to transcriptional targeting, and (iii) To evaluate the efficiency of imaging in vivo the expression of prostate cancer specific transcripts by using transcriptome-directed promoters cloned into RGD/GRP78-targeted AAVP constructs. The concept of establishing a panel of multiple markers is in line with the much heralded era of personalized medicine, and should launch, for the first time, a system for imaging temporally and spatially, in vivo, the transcriptional profile within tumors.

描述（由申请人提供）：转录分析，靶向癌细胞和分子遗传成像中的整合将具有许多生物学应用，并且具有改善医学实践的潜力。我们设计并验证了一种新的杂种病毒系统，该病毒系统由腺相关病毒（AAV）和噬菌体（称为AAVP）组成。这些配体指导的颗粒可实现针对性的全身性传递和转基因记者的成像。可以遵循对报告基因反式激活的实验性非侵入性监测，可以遵循前体和体内。靶向分子成像将代表前列腺癌管理的重大进步。该项目的总体目标是将AAVP的归巢和肿瘤转导能力与癌症特异性启动子相结合，作为基于选定标记物的转录活性开发改进的肿瘤监测工具的一种方法。这些启动子将通过对公共数据库中的广泛搜索以及鼠尾草文库的构建和大规模测序进行大规模的癌细胞和肿瘤脉管系统的转录组进行大规模评估，并使用现代的低成本高成本高成本高成本高成本的高成本高素质pyrput pyrosequencing方法来确定。已确定的上调基因将在两个独立的样本集中进行验证，并将确认的上调的成绩单的启动子被识别，认证并克隆到AAVP中。通过对一组可靠基因的定义，我们期望拥有全面的肿瘤标记面板，涵盖了不同患者肿瘤样品中大多数基因表达变异性。建立多个标记面板的概念与众多的个性化医学时代一致，并且应该首次启动一个用于时间和空间上的系统，即体内，即肿瘤中的转录曲线。旨在靶向肿瘤的媒介的矢量组合，该肽在肿瘤特异性启动子的控制下还携带自杀/报告基因转基因（HSVTK），应以非常特定的方式实现转录成像和肿瘤生长抑制。该载体的成像和治疗可能性加强了药物诊断共同开发的概念，如果先于对基因表达的个体评估（例如，在前列腺癌患者的尿液中），可能会导致基于个体患者上诉标记的个性化诊断/治疗。这种个性化的成像测试与伴侣药物合并在一起，以及最近由美国食品药品管理局提出的药物诊断共同开发概念。在这种视力下，特定肿瘤基因提供的转录成像也将引发肿瘤凋亡，从而允许成像以及治疗和监测疾病进展。我们的具体目的是：（i）使用大规模的转录组分析来识别和验证前列腺癌中上调的转录本。 （ii）将AAVP的配体定向靶向转录靶向组合，（iii）通过使用克隆到RGD/GRP78对准的AAVP构造中的转录组指导的启动​​子来评估体内成像的效率。建立多个标记面板的概念与众多的个性化医学时代一致，并且应该首次启动一个用于时间和空间上的系统，即体内，即肿瘤中的转录曲线。