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

项目概要-总体 来自City of Hope的胶质母细胞瘤（GBM）治疗网络（GTN）U19应用的总体目标是， 翻译基因组学研究所和亚拉巴马大学伯明翰分校正在开发上级 GBM是成人中最常见和最具侵袭性的原发性脑肿瘤。有效 治疗仍然难以捉摸，并且患者很少用标准疗法治愈。GTN U19应用 体现了一种独特的方法组合，旨在显着推进患者的治疗， 通过解决肿瘤异质性、血脑屏障穿透和免疫抑制性GBM 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GBM成人患者的I期临床研究。每个 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。 使用特征引导评估和治疗的代理。这些项目的具体目标是： 项目1。开发和临床测试工程溶瘤疱疹病毒表达完整的- 长度抗CD 47单克隆抗体用于治疗GBM。 项目2.开发和临床试验他喹莫德作为辅助药物，以增强 围手术期施用抗GBM免疫疗法。 项目3。开发和临床测试分子“脆弱性特征”指导治疗 用neddylation抑制剂pevonedistat治疗GBM。 此外，U19申请提出了解决药物开发中主要障碍的策略， 结合两种创新的研究工具：1）脑内微透析，合理选择合适的 用于在GBM患者中进行测试的全身施用的疗法和2）下一代外显子组和转录组 测序，以确定分子“脆弱性特征”，可以指导适当的患者选择， 临床试验入组。这些分析能力将使我们能够量化CNS药物渗透和解剖 在拟议的临床试验中，肿瘤和基质细胞的基因组异质性。此外，两个拟议项目 利用City of Hope的GMP设施生产生物制剂和小分子， 首次在成人GBM患者中进行。 综上所述，本申请中的创新项目和共享资源核心联合收割机结合了我们在以下方面的优势： 基础，转化和临床研究在一个高度协作的环境，促进思想的共享， 结果，资源和临床人群，以开发GBM的有效治疗方法。如果成功，生成的数据 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 从而避免肿瘤异质性和免疫抑制。

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.