Molecular Profiling and Bioinformatics

分子分析和生物信息学

• 批准号: 10488209
• 负责人: MICHAEL E. BERENS
• 金额: $ 13.11万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 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/10488209
• 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; 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; 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

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.

项目概要-核心B U19分子特征分析和生物信息学核心（核心B）将提供最先进的基因组学和 生物信息技术和专业知识，以推进希望之城U19计划的每个项目。在 为了完成胶质母细胞瘤转化网络（GTN）的更大使命，核心B将 提供CAP认证、CLIA批准的外显子组和转录组测序，为患者护理返回数据 决策的核心B桥接胶质母细胞瘤易感性的分子决定因素的实验室发现， 在U19和临床环境中的三种新型药物，其中精确使用这些治疗可能具有 使患者受益的可能性最大。核心B将通过以下方式实现：A）提供全面的CLIA认证 对参加U19临床试验的患者进行基因组分析，以及对临床前 模型，并提供单细胞/细胞核转录组学分析的收获细胞浸润收集从 切除后的瘤床或分散的组织。这些研究将提供对肿瘤 异质性、肿瘤敏感性或抗性以及肿瘤演变。B）识别易受攻击性的特征， 正在评估的代理人。对于项目1，将分析GBM外显子组和转录组数据，以确定 改变对溶瘤性疱疹病毒感染的易感性的特征，发挥作用的基因的等位基因的影响， 在HSV复制中的作用，以及患者肿瘤的去卷积，以描绘包含所述抗体的宿主细胞浸润。 入组溶瘤治疗的同系模型和胶质瘤患者的治疗前微环境免疫状态 病毒/抗CD-47临床试验。对于项目2，来自入组研究的患者的肿瘤的外显子组和转录组数据 评估他喹莫德的临床试验将被去卷积以辨别免疫细胞浸润的群体 与手术收集的切除腔液的治疗后单细胞转录组学分析相比， 放置导管。来自接受不同治疗的同基因神经胶质瘤模型的肿瘤将通过单克隆抗体分析。 用于细胞去卷积的核转录组学。对于项目3，我们将进一步开发协同签名， GBM对pevonedistat +依托泊苷联合治疗的易感性，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以及 依托泊苷（TOP 2A抑制剂）与pevonedistat的协同活性。C）。提供最先进的生物医学 信息学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，从临床前和临床数据中获得最高价值， 项目核心项目B还将促进与各个项目/核心项目的数据和信息交流与合作 在GTN。核心B的长期目标是参与设计、开发和采用 适应性，签名指导的伞形临床试验，支持GTN中出现的所有新治疗方法。