Development of Small Molecule Inhibitors and Biologic Agents for Treatment of Glioblastoma Using Intracerebral Microdialysis and Signatures of Vulnerability

利用脑内微透析和脆弱性特征开发用于治疗胶质母细胞瘤的小分子抑制剂和生物制剂

• 批准号: 10488199
• 负责人: Behnam Badie
• 金额: $ 92.09万
• 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/10488199
• 关键词: Address; Adult; Alabama; Anti-CD47; Antibody Therapy; Basic Science; Bioinformatics; Biological; Biological Products; Blood - brain barrier anatomy; Cities; Clinical; Clinical Research; Clinical Trials; Collaborations; Correlative Study; Cyclic GMP; Data; Development; Engineering; Genomics; Glioblastoma; Goals; Herpesviridae; Heterogeneity; Immunomodulators; Immunosuppression; Immunotherapy; Institution; Laboratories; Laboratory Scientists; Length; Methods; Microdialysis; Molecular; Molecular Profiling; Monoclonal Antibodies; New Agents; Oncolytic; Oncolytic viruses; Pathway interactions; Patient Selection; Patients; Penetration; Pharmaceutical Preparations; Phase; Phase I Clinical Trials; Population; Primary Brain Neoplasms; Research; Research Activity; Research Institute; Research Project Grants; Resource Sharing; Resources; Services; Site; Stromal Cells; Techniques; Testing; Therapeutic; Therapeutic Agents; Time; Translating; Translational Research; Universities; Work; base; blood-brain barrier penetration; clinical trial enrollment; design; drug development; drug testing; effective therapy; exome; exome sequencing; experience; immunopharmacology; improved; inhibitor; innovation; interest; neoplastic cell; next generation; novel; novel therapeutics; preclinical development; preclinical study; single cell sequencing; small molecule; small molecule inhibitor; tool; transcriptome; transcriptome sequencing; translational genomics; tumor heterogeneity; tumor microenvironment

PROJECT SUMMARY - OVERALL The overall goal of this Glioblastoma (GBM) Therapeutics Network (GTN) U19 application from City of Hope, Translational Genomics Research Institute, and University of Alabama at Birmingham is to develop superior treatments for patients with GBM, the most common and aggressive primary brain tumors in adults. Effective treatments remain elusive and patients are rarely cured with standard therapies. This GTN U19 application embodies a unique combination of approaches designed to significantly advance the treatment of patients with GBM by addressing tumor heterogeneity, blood-brain barrier penetration, and the immunosuppressive GBM tumor microenvironment. The three proposed research projects will translate therapeutic agents from preclinical development, through IND-enabling studies, and into phase I clinical studies in adult patients with GBM. Each project is based on novel molecular preclinical studies with small-molecule inhibitors and immunomodulatory agents that use signature-guided assessment and treatments. Specific goals of the projects are: Project 1. Develop and clinically test an engineered oncolytic herpes virus expressing a full- length anti-CD47 monoclonal antibody for treatment of GBM. Project 2. Develop and clinically test tasquinimod as an adjunct to enhance the efficacy of anti-GBM immunotherapies administered peri-operatively. Project 3. Develop and clinically test a molecular “signatures of vulnerability” guided treatment of GBM with neddylation inhibitor pevonedistat. In addition, this U19 application proposes strategies that will address major barriers in drug development by incorporating two innovative research tools: 1) intracerebral microdialysis to rationally select appropriate systemically administered therapies for testing in GBM patients and 2) next generation exome and transcriptome sequencing to identify molecular “signatures of vulnerability” that can guide appropriate patient selection for clinical trial enrollment. These analytical capabilities will enable us to quantify CNS drug penetration and dissect genomic heterogeneity in tumor and stromal cells in the proposed clinical trials. Also, two of the proposed projects leverage City of Hope’s GMP facilities to manufacture biological agents and small molecules that will be tested in adult GBM patients for the first time. In summary, the innovative projects and shared resources cores in this application combine our strengths in basic, translational, and clinical research in a highly collaborative setting that promotes the sharing of ideas, results, resources, and clinical populations to develop effective treatments for GBM. If successful, data generated by these studies have the potential to transform the treatment of adult GBM patients by introducing new agents that circumvent tumor heterogeneity and immunosuppression.

项目摘要 - 总体 该胶质母细胞瘤（GBM）治疗网络（GTN）U19的总体目标是希望之城的应用 转化基因组学研究所和伯明翰的阿拉巴马大学将发展出色 GBM患者的治疗方法，这是成年人中最常见和最具侵略性的原发性脑肿瘤。有效的 治疗仍然难以捉摸，患者很少使用标准疗法治愈。此GTN U19应用程序 体现了一种独特的方法组合，旨在显着推进患者的治疗 GBM通过解决肿瘤异质性，血脑屏障渗透和免疫抑制GBM 肿瘤微环境。提出的三个研究项目将转化临床前的治疗剂 开发通过辅助研究，并在成年患者的I期临床研究中开发。每个 项目基于具有小分子抑制剂和免疫调节的新分子临床前研究 使用签名引导评估和治疗的代理。项目的具体目标是： 项目1。开发和临床测试一种工程化的溶瘤疱疹病毒，表达了全面的 长度抗CD47单克隆抗体用于治疗GBM。 项目2。开发和临床测试tasquinimod作为提高效率的辅助 抗GBM免疫疗法术受到术术。 项目3。开发和临床测试分子“脆弱性”指导治疗 带有Neddylation抑制剂Pevonedistat的GBM的GBM。 此外，该U19申请提案策略将通过 合并两个创新的研究工具：1）脑外微透析以合理选择适当 系统地给予GBM患者测试的疗法和2）下一代外显子组和转录组 测序以识别可以指导适当患者选择的分子“脆弱性” 临床试验入学。这些分析能力将使我们能够量化CNS药物穿透并进行剖析 在拟议的临床试验中，肿瘤和基质细胞中的基因组异质性。另外，有两个拟议的项目 利用希望城市的GMP设施来制造将要测试的生物剂和小分子 首次在成年GBM患者中。 总而言之，本应用程序中创新的项目和共享资源核心将我们的优势结合在一起 在高度协作的环境中，基本，翻译和临床研究促进了思想的共享， 结果，资源和临床人群为GBM开发有效的治疗方法。如果成功，数据生成 通过这些研究，有可能通过引入新药物来改变成人GBM患者的治疗 这种规避肿瘤异质性和免疫抑制。