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: 10696180
• 负责人: Behnam Badie
• 金额: $ 91.77万
• 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/10696180
• 关键词: Address; Adult; Adult Glioblastoma; Alabama; Anti-CD47; Antibody Therapy; Basic Science; Bioinformatics; Biological; Biological Products; Cities; Clinical; Clinical Research; Clinical Trials; Collaborations; Correlative Study; Cyclic GMP; Data; Development; Educational process of instructing; Engineering; Genomics; Glioblastoma; Goals; Herpesviridae; Heterogeneity; 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; Perioperative; 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; blood-brain barrier crossing; blood-brain barrier penetration; clinical trial enrollment; design; drug development; drug testing; effective therapy; exome; exome sequencing; experience; immune modulating agents; immunopharmacology; improved; inhibitor; innovation; interest; manufacture; 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.

项目总结--总体 来自希望之城的胶质母细胞瘤(GBM)治疗网络(GTN)U19应用的总体目标是， 翻译基因组研究所和阿拉巴马大学伯明翰分校正在开发优越的 治疗基底膜是成人中最常见和最具侵袭性的原发脑瘤。有效 治疗方法仍然难以捉摸，患者很少能用标准疗法治愈。此GTN U19应用程序 体现了一种独特的方法组合，旨在显著提高患者的治疗 通过解决肿瘤异质性、血脑屏障穿透和免疫抑制的基底膜 肿瘤微环境。这三个拟议的研究项目将把临床前的治疗药物 开发，通过IND使能研究，并进入成人GBM患者的I期临床研究。每个人 该项目基于小分子抑制剂和免疫调节剂的新分子临床前研究 使用签名指导评估和治疗的代理。这些项目的具体目标是： 项目1.开发和临床测试一种表达完整的- 长链抗CD47单抗治疗基底膜。 项目2.开发和临床试验他克莫特作为辅助药物，以提高患者的疗效 围手术期给予抗GBM免疫治疗。 项目3.开发和临床测试一种分子“易损性签名”指导治疗 肾小球滤过率(GBM)加去甲肾上腺素。 此外，这项U19申请提出的战略将解决药物开发中的主要障碍，方法是 结合两个创新的研究工具：1)脑内微透析，合理选择合适的 用于检测GBM患者的系统管理疗法和2)下一代外显子组和转录组 通过测序来识别分子“易损性特征”，从而指导适当的患者选择 临床试验招生。这些分析能力将使我们能够量化中枢神经系统药物的渗透和解剖 拟议的临床试验中肿瘤和间质细胞的基因组异质性。此外，拟议中的两个项目 利用希望之城的GMP设施生产将进行测试的生物制剂和小分子 首次在成人GBM患者中发现。 总而言之，此应用程序中的创新项目和共享资源核心结合了我们在 在促进思想共享的高度协作环境中进行基础、转化和临床研究， 结果、资源和临床人群，以开发有效的GBM治疗方法。如果成功，则生成数据 通过这些研究，有可能通过引入新的药物来改变成人GBM患者的治疗方式 避免了肿瘤的异质性和免疫抑制。