Molecular Profiling and Bioinformatics

分子分析和生物信息学

基本信息

批准号：
10306303
负责人：
MICHAEL E. BERENS
金额：
$ 13.09万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-13 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10306303
关键词：
Adoption Aftercare Alleles Aneuploidy Anti-CD47 Antibodies Beds Bioinformatics Biological Products CLIA certified Catheters Cell Nucleus Cells Characteristics Cities Clinic Clinical Clinical Data Clinical Trials Collaborations Consultations DNA sequencing Data Data Analytics Data Set Decision Making Development Effectiveness Eligibility Determination Engineering Enrollment Ensure Etoposide Evolution Excision Fostering Future Gene Expression Profiling Genes Genomics Glioblastoma Glioma Goals Harvest Herpesviridae Individual Infection Infrastructure Intervention Laboratories Lead Liquid substance Loss of Heterozygosity Lymphocyte Machine Learning Manuscripts Methods Microdialysis Mission Modeling Molecular Molecular Profiling Mus Mutation Normal tissue morphology Oncolytic Oncolytic viruses Operative Surgical Procedures PTEN gene Patient Care Patients Phenotype Play Population Pre-Clinical Model Predisposition Process RNA Reporting Research Research Personnel Research Project Grants Resistance Resources Role Running Sampling Secure Services Simplexvirus Single Nucleotide Polymorphism Specimen Structure Surgically-Created Resection Cavity TOP2A gene Techniques Technology Testing The Cancer Genome Atlas Therapeutic Therapeutic Intervention Tissue-Specific Gene Expression Tissues Transcript Tumor Tissue Tumor-infiltrating immune cells Variant Virus Diseases Work Writing base bioinformatics pipeline bioinformatics tool biomedical informatics design exome exome sequencing experimental study feature selection genomic data immunological status immunopharmacology improved improved outcome inhibitor/antagonist insight novel patient derived xenograft model pre-clinical preclinical study programs response small molecule inhibitor synergism transcriptome transcriptome sequencing transcriptomics tumor tumor heterogeneity tumor-immune system interactions

项目摘要

PROJECT SUMMARY – CORE B The U19 Molecular Profiling and Bioinformatics Core (Core B) will provide state-of-the-art genomics and bioinformatics technology and expertise to advance each of the projects in the City of Hope U19 program. In anticipation of delivering on the larger mission of the Glioblastoma Translational Network (GTN), Core B will provide CAP-certified, CLIA-approved exome and transcriptome sequencing that returns data for patient care decision-making. Core B bridges bench discovery of molecular determinants of glioblastoma vulnerability to the three novel agents in this U19 and the clinical setting, in which precision use of these treatments may have the highest likelihood of benefiting patients. Core B will achieve this by: A) Providing comprehensive CLIA-certified genomic profiling for patients enrolled on our U19 clinical trials, as well as genomic sequencing of preclinical models, and offering single cell/nuclei transcriptomic analyses of harvested cell infiltrates collected from the tumor bed following resection or dispersed tissue. These studies will provide granular insight into tumor heterogeneity, tumor sensitivity or resistance, and tumor evolution. B) Identifying signatures of vulnerability to the agents being evaluated. For Project 1, GBM exome and transcriptomic data will be analyzed to identify features that modify susceptibility to oncolytic herpes virus infection, the impact of alleles of genes that play a role in HSV replication, and deconvolution of patient tumors to depict the host cell infiltrate comprising the pretreatment microenvironment immune status of syngeneic models and glioma patients enrolled in the oncolytic virus/anti CD-47 clinical trial. For Project 2, exome and transcriptome data from tumors of patients enrolled in the clinical trial evaluating tasquinimod will be deconvoluted to discern populations of immune cell infiltrates to compare with post-treatment single cell transcriptomic analysis of resection cavity fluid collected from surgically placed catheters. Tumors from syngeneic glioma models receiving different treatments will analyzed by single nuclei transcriptomics for cell deconvolution. For Project 3, we will further develop a synergy signature indicative of GBM vulnerability to the combination of pevonedistat + etoposide, leading to a patient-enrichment strategy for future clinical trials. Preliminary data indicates that PTEN status (copy number, mutation, expression levels) serves as a determinant for likelihood of response to the neddylation inhibitor, pevonedistat, as well as the synergistic activity of etoposide (TOP2A inhibitor) with pevonedistat. C). Deliver state-of-the-art biomedical informatics and data analytics expertise and services. Core B will provide state-of-the-art bioinformatics methods, including machine learning techniques, to derive highest value from the preclinical and clinical data in each project. Core B will also foster data and information exchange and collaboration with individual Projects/Cores across the GTN. The long term goal of Core B is to participate in the design, development, and adoption of an adaptive, signature-guided umbrella clinical trial supporting all new treatments emerging from the GTN.

项目摘要 - 核心B U19分子分析和生物信息学核心（核心B）将提供最新的基因组学和生物信息学技术和专业知识，以推进Hope U19计划中的每个项目。在期望交付胶质母细胞瘤转化网络（GTN）的更大使命，核心B将提供经过帽认证的，CLIA批准的外观和转录组测序，以返回患者护理的数据决策。 Core B Bridges板凳发现胶质母细胞瘤脆弱性的分子决定剂 U19和临床环境中的三种新型药物，其中这些治疗方法的精确使用可能具有受益于患者的可能性最高。核心B将通过：a）提供全面的CLIA认证参加U19临床试验的患者的基因组分析以及临床前的基因组测序模型，并提供从收集的收获细胞浸润的单细胞/核转录组分析切除或分散组织后的肿瘤床。这些研究将为肿瘤提供颗粒状的洞察力异质性，肿瘤敏感性或抗性以及肿瘤的演变。 b）确定脆弱性的签名被评估的代理。对于项目1，将分析Exome和转录组数据以识别改变了对溶瘤疱疹病毒感染的敏感性的特征，这是发挥作用的基因等位基因的影响在HSV复制中的作用和患者肿瘤的反卷积描述宿主细胞浸润完成在溶瘤癌症患者和神经胶质瘤患者的预处理微环境免疫状态病毒/抗CD-47临床试验。对于项目2，来自入学的患者肿瘤的外显子组和转录组数据评估tasquinimod的临床试验将被解卷，以辨别免疫细胞浸润的种群与从外科手术收集的切除腔液的治疗后单细胞转录组分析进行比较放置导管。来自合成性神经胶质瘤模型接受不同治疗方法的肿瘤将通过单一分析细胞反卷积的核转录组学。对于项目3，我们将进一步开发协同签名指示性 GBM与pevonedistat +依托泊苷组合的脆弱性，导致患者富集策略未来的临床试验。初步数据表明PTEN状态（拷贝数，突变，表达水平）作为对neddylation抑制剂pevonedistat的反应可能性的决定者依托泊苷（TOP2A抑制剂）与pevonedistat的协同活性。 c）。提供最先进的生物医学信息和数据分析专业知识和服务。核心B将提供最先进的生物信息学方法，包括机器学习技术，以从每种临床前和临床数据中获得最高价值项目。核心B还将促进数据和信息交流以及与单个项目/核心的合作穿过GTN。核心B的长期目标是参与设计，开发和采用自适应，签名引导的雨伞临床试验，支持GTN中出现的所有新疗法。