Molecular Profiling and Bioinformatics

分子分析和生物信息学

• 批准号: 10696184
• 负责人: MICHAEL E. BERENS
• 金额: $ 17.52万
• 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/10696184
• 关键词: Accreditation; Adoption; Aftercare; Alleles; Aneuploidy; Anti-CD47; Antibodies; Beds; Bioinformatics; Biological Products; CLIA certified; Catheters; Cell Nucleus; Cells; Certification; Characteristics; Cities; Clinic; Clinical; Clinical Data; Clinical Trials; Collaborations; Consultations; DNA sequencing; Data; Data Analytics; Data Reporting; 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; Herpesviridae Infections; Individual; Infection; Infiltration; 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; Population; Pre-Clinical Model; Predisposition; Process; RNA; Research; Research Personnel; Research Project Grants; Resistance; Resources; 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; Variant; Work; Writing; bioinformatics pipeline; bioinformatics tool; biomedical informatics; design; exome; exome sequencing; experimental study; feature selection; genomic data; genomic profiles; immune cell infiltrate; immunological status; immunopharmacology; improved; improved outcome; inhibitor; insight; novel; participant enrollment; 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.

项目摘要--核心B U19分子图谱和生物信息学核心(核心B)将提供最先进的基因组学和 生物信息学技术和专业知识，以推进希望之城U19计划中的每个项目。在……里面 预期实现胶质母细胞瘤翻译网络(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。核心B连接了胶质母细胞瘤易感性的分子决定因素的台式发现 三种新药在U19和临床环境中的精确使用，在这些治疗中可能会有 使患者受益的可能性最高。核心B将通过以下方式实现这一目标：A)提供全面的CLIA认证 参加我们U19临床试验的患者的基因组图谱，以及临床前的基因组测序 模型，并提供从收集的细胞浸润物的单细胞/核转录分析 切除后的肿瘤床或分散的组织。这些研究将提供对肿瘤的细粒度洞察 异质性、肿瘤敏感性或耐药性，以及肿瘤的演变。B)确定易受攻击的签名 正在评估的代理。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复制和患者肿瘤去卷积中的作用，以描绘宿主细胞浸润物，包括 同基因模型和脑胶质瘤患者溶瘤前的微环境免疫状况 病毒/抗CD-47临床试验。对于项目2，来自登记的患者的肿瘤的外显子组和转录组数据 评估他喹莫特的临床试验将被解开，以辨别免疫细胞浸润物的群体 手术切除腔液与治疗后单细胞转录分析的比较 放置导尿管。接受不同治疗的同基因胶质瘤模型的肿瘤将进行单项分析 用于细胞去卷积的核转录学。对于项目3，我们将进一步开发协同签名指示 对pevoneDistat+依托泊苷联合使用的GBM脆弱性的研究，导致患者对 未来的临床试验。初步数据显示PTEN状态(拷贝数、突变、表达水平) 作为对糖尿病抑制剂pevoneDistat的反应的可能性的决定因素，以及 依托泊苷(TOP2A抑制剂)与培非地塞特的协同作用。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，以从每个临床前和临床数据中获得最高价值 项目。核心B还将促进与个别项目/核心的数据和信息交流与合作 跨越GTN。核心B的长期目标是参与设计、开发和采用 适应性、签名指导的伞式临床试验支持GTN出现的所有新疗法。