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.

项目概要 - 总体 City of Hope 的胶质母细胞瘤 (GBM) 治疗网络 (GTN) U19 应用程序的总体目标， 转化基因组学研究所和阿拉巴马大学伯明翰分校将开发卓越的 对成人中最常见和最具侵袭性的原发性脑肿瘤 GBM 患者的治疗有效。 治疗方法仍然难以捉摸，而且患者很少能通过这种 GTN U19 应用治愈。 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、血脑屏障穿透性和免疫抑制性 GBM 肿瘤微环境。三个拟议的研究项目将从临床前转化治疗药物。 通过 IND 授权研究进行开发，并进入成人 GBM 患者的 I 期临床研究。 该项目基于小分子抑制剂和免疫调节剂的新型分子临床前研究 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. 开发并临床测试一种表达全基因工程的溶瘤疱疹病毒 用于治疗GBM的长度抗CD47单克隆抗体。 项目2.开发并临床测试他喹莫德作为辅助药物以增强疗效 围手术期进行抗 GBM 免疫治疗。 项目 3. 开发并临床测试分子“脆弱性特征”指导治疗 GBM 与 neddylation 抑制剂 pevonedistat。 此外，该 U19 申请提出了通过以下方式解决药物开发中主要障碍的策略： 结合两种创新研究工具：1）脑内微透析，合理选择合适的 用于 GBM 患者测试的系统性治疗方法和 2) 下一代外显子组和转录组 测序以确定分子“脆弱性特征”，从而指导适当的患者选择 这些分析能力将使我们能够量化中枢神经系统药物渗透和剖析。 拟议的临床试验中肿瘤和基质细胞的基因组异质性此外，还有两个拟议的项目。 利用 City of Hope 的 GMP 设施生产将进行测试的生物制剂和小分子 首次在成年 GBM 患者中进行研究。 综上所述，该应用中的创新项目和共享资源核心结合了我们在以下方面的优势： 在高度协作的环境中进行基础、转化和临床研究，促进思想共享， 结果、资源和临床人群，以开发 GBM 的有效治疗方法 如果成功，将生成数据。 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 规避肿瘤异质性和免疫抑制。