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，在生物信息学、临床前癌症建模、高通量基因和化学文库筛选方面具有卓越的能力，在大型、多机构研究计划中具有丰富的参与和领导能力。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性的工作流程，该工作流程将由癌症靶标发现和开发网络转发。在这一应用中，Silico卓越研究中心(ISRCE)的TGen‘s提供了关于多形性胶质母细胞瘤(GBM)的癌症基因组图谱(TCGA)的工作知识，并提供了用于数据库挖掘的生物信息学工具和工作计划，用于肿瘤亚型和目标识别。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(目标1)确定的候选靶进一步使用54个分子轮廓的人原位原发GBM异种移植物进行通知。这些信息平台及其注释的工作流管理系统指导桑福德-伯纳姆医学研究所(SBMRI)在目标和路径验证(AIM 2)和可处理性(AIM 3)方面的功能工作。SBMRI的化学基因组学中心[NIH分子文库探针生产中心网络(MLPCN)的综合中心和NCI的化学生物学联盟]实现了强大的RNAi和基于小分子的高通量分析开发和筛选，以有效地对目标和途径进行大规模功能验证。结果将被用于迭代增强分类和预测算法，然后我们改进的生物信息学工具可用于识别CTD2网络转发的其他肿瘤类型中具有生物学意义的靶点。因此，这项建议的意义源于领先的生物医学研究组织在癌症分子亚类中识别和验证易处理靶标的独特集成，包括计算机技术和实验室技术。项目的创新 我们的多学科团队反复询问胶质母细胞瘤和其他癌症的良好特征、临床相关的临床前模型，强调了这一点。总体而言，我们描述了一种利用胶质母细胞瘤生物学和建模方面的顶尖人才的系统性方法，识别肿瘤亚群以及靶点和途径的生物信息学方法，以及专注于癌症关键特征的大量高通量分析方法，适合在相关临床前模型中进行有效的靶点验证。此外，我们的小分子化合物筛选针对已识别的目标和途径提供了潜在的快速通道，用于针对已验证的目标的新型“微扰剂”。因此，所描述的项目将通过展示一种易于处理的目标识别和验证的有效方法来影响信息学、癌症生物学和药物发现领域，从而加速将基因组发现转化为新的治疗方法。

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.