Systematic Development of Novel, Druggable Cancer Targets

描述（由申请人提供）：我们是一个多学科团队，具有生物信息学，临床前癌症建模，高通量遗传和化学文库筛选的能力，具有参与和领导大型多机构研究计划的传统。我们的提案描述了系统地识别、验证和评估胶质母细胞瘤和其他癌症的新靶点的可药物性的工作流程，这些靶点将由癌症靶点发现和开发（CTD2）网络转发。具体来说，在这个应用程序中，TGen的卓越硅研究中心（ISRCE）提供了关于多形式胶质母细胞瘤（GBM）的癌症基因组图谱（TCGA）的工作知识，并带来了生物信息学工具和工作计划，用于肿瘤亚组和目标识别的数据库挖掘。系统生物学专业知识由Van Andel Research Institute （VARI）和Thompson Reuters （GeneGO）提供。通过信息学策略（Aim 1）确定的候选靶点，使用54个分子谱的人类原位原发性GBM异种移植物进一步了解。这些信息平台及其注释的工作流管理系统指导了斯坦福-伯纳姆医学研究所（SBMRI）在目标和途径验证（Aim 2）和可追溯性（Aim 3）方面的功能工作。SBMRI的化学基因组学中心[美国国立卫生研究院分子文库探针生产中心网络（MLPCN）和NCI化学生物学联盟的综合中心]能够实现强大的RNAi和基于小分子的高通量分析开发和筛选，以有效地大规模功能验证靶标和途径。研究结果将用于迭代地增强分类和预测算法，我们改进的生物信息学工具随后可用于识别CTD2网络转发的其他肿瘤类型的生物学重要靶点。因此，这项提议的意义源于领先的生物医学研究组织对癌症分子亚群中易于处理的靶标识别和验证的敏锐的计算机和实验室技术的独特整合。项目的创新

DESCRIPTION (provided by applicant): We are a multidisciplinary team with demonstrated competencies in bioinformatics, preclinical cancer modeling, high throughput genetic and chemical library screening, with a legacy of participation as well as leadership in large, multi-institutional research initiatives. Our proposal depicts workflows that systematically identify, validate, and assess druggability of novel targets in glioblastoma and other cancers to be forwarded by the Cancer Target Discovery and Development (CTD2) Network. Specifically in this application, TGen's In Silico Research Center of Excellence (ISRCE) provides working knowledge of The Cancer Genome Atlas (TCGA) on Glioblastoma Multiforme (GBM), and brings bioinformatic tools and workplans for database mining for tumor subgrouping and target identification. Systems biology expertise is provided by the Van Andel Research Institute (VARI) and Thompson Reuters (GeneGO). Candidate targets identified by informatics strategies (Aim 1) are further informed using 54 molecularly profiled human orthotopic primary GBM xenografts. These informatic platforms and their annotated Workflow Management Systems guide functional work in target and pathway validation (Aim 2) and tractability (Aim 3) at Sanford-Burnham Medical Research Institute (SBMRI). SBMRI's Center for Chemical Genomics [a Comprehensive Center in NIH's Molecular Libraries Probe Production Centers Network (MLPCN) and NCI's Chemical Biology Consortium] enable robust RNAi and small-molecule-based high-throughput assay development and screening for efficient large-scale functional validation of targets and pathways. Results will be utilized to iteratively enhance classification and prediction algorithms~ our refined bioinformatic tools are then available for identification of biologically significant targets in other tumor types forwarded by the CTD2 Network. Thus, the significance of this proposal stems from the unique integration of incisive in silico and laboratory technologies by leading biomedical research organizations for tractable target identification and validation in molecular subsets of cancers. The innovation of the project is underscored by our multi-disciplinary team iteratively interrogating well-characterized, clinically-relevant preclinical models of glioblastoma and other cancers. Overall, we describe a systematic approach that leverages top-tiered talent in the biology and modeling of glioblastoma, bioinformatic methodologies to identify tumor subgroups as well as targets and pathways, and an expansive repertoire of high throughput assays focused on key hallmarks of cancer suitable for efficient target validation in relevant preclinical models. Furthermore, our us of small-molecule compound screens against identified targets and pathways provides a potential fast-track for novel "perturbagens" against the validated targets. As such, the described project will impact the fields of informatics, cancer biology and drug discovery by demonstrating an efficient approach for tractable target identification and validation, thereby accelerating the translation of genomic discoveries into new treatments. PUBLIC HEALTH RELEVANCE: The human genome project and allied molecular depictions of human cancer allow computer mining of possible vulnerabilities of cancer. We describe a workplan by which specific candidate therapy targets in cancer are identified, validated, then utilized to find molecules that could point to new cancer drugs.