Harvard/Stanford GTN Program: Novel targeted therapeutics for glioblastoma

哈佛/斯坦福 GTN 项目：胶质母细胞瘤的新型靶向疗法

• 批准号: 10491787
• 负责人: Tracy T Batchelor
• 金额: $ 85.99万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-21 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10491787
• 关键词: Address; Adult; Adult Glioblastoma; Agar; Age-Years; Anabolism; Anaplastic astrocytoma; Astrocytoma; Basic Science; Biometry; Brain; Cancer Center; Cancer Etiology; Cancer Patient; Cause of Death; Cells; Cessation of life; Clinical; Clinical Pharmacology; Clinical Sciences; Clinical Trials; Clinical Trials Design; Collaborations; Communication; Communities; DHODH gene; Data; Doctor of Medicine; Drug Monitoring; Enzymes; Epidermal Growth Factor Receptor; Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor; Failure; Funding; Funding Opportunities; Generations; Genomics; Glioblastoma; Glioma; Glutamates; Goals; Image; Institution; Lead; Ligands; Magnetic Resonance Spectroscopy; Malignant Neoplasms; Metabolic; Methodology; Modeling; Mutation; National Cancer Institute; Nervous system structure; Neurons; Neurosciences; Non-Small-Cell Lung Carcinoma; Operative Surgical Procedures; Pathogenesis; Pathogenicity; Pathway interactions; Patients; Penetrance; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Plasma; Population; Pre-Clinical Model; Principal Investigator; Prodrugs; Protocols documentation; Pyrimidine; Research Personnel; Research Project Grants; Resources; Role; Science; Scientist; Services; Signal Transduction; Specific qualifier value; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Sum; Synapses; Testing; Therapeutic; Time; Tissues; Translational Research; Wit; Woman; Work; antagonist; base; cancer genetics; cancer imaging; cell type; clinical efficacy; clinical material; cost effective; early phase clinical trial; experience; feeding; imaging facilities; improved; inhibitor; insight; lead optimization; mass spectrometric imaging; men; middle age; mutant; neoplastic cell; neuropathology; new therapeutic target; novel; preclinical development; programs; ranpirnase; response; single-cell RNA sequencing; skills; small molecule; small molecule therapeutics; structural biology; translational scientist; tumor; tumor addiction; tumor growth

We respond here to a Funding Opportunity Announcement (FOA) for multi-institutional teams to form a Glioblastoma Therapeutics Network (GTN). Basic scientists and clinical/translational investigators from three institutions in the Dana-Farber/Harvard Cancer Center (DF/HCC) have joined forces with their counterparts in the Stanford Cancer Center (SCC) to create the “Harvard/Stanford GTN”. UT Southwestern is also represented in one key collaboration. Distinctive features of this bi-coastal GTN include (i) broad and deep expertise in brain-penetrant, small molecule therapeutics and (ii) a strong presence in the emerging field of Cancer Neuroscience – a field that addresses the central role of the nervous system in glioblastoma pathogenesis. Our objective is to improve the treatment of adult glioblastomas (GBMs) and Astrocytoma, IDH- mutant, grade 4 by taking novel, effective, brain-penetrant small molecule drugs through lead optimization, to preclinical development and into early phase clinical trials. Our study plan features three projects: Project 1 targets metabolic reprogramming in Astrocytoma, IDH mutant, grade 4. Project 2 targets the constitutive, ligand-independent EGFR signaling observed in more than 50% of adult IDH wild-type GBM. Project 3 targets a recently appreciated forward-feeding gliomagenic loop between tumor cells and electrically active neurons in IDH wild-type adult glioblastomas. All three projects feature surgical window clinical trials of brain-penetrant drugs that are hitherto untested in GBM. In addition, Project 2 will develop novel allosteric inhibitors that promise to address a shortcoming of all current EGFR antagonists as GBM therapeutics – to wit, lack of a therapeutic window. Insights from clinical trials will be enhanced by a Pharmacological and Genomic Imaging Core (PGIC). This core will allow our trialists to monitor drug impact on glioblastoma cell populations using specialized single cell RNAseq protocols. Drug penetrance within tumors and drug-induced changes in key metabolites will be visualized using matrix assisted laser desorption ionization mass spectrometry imaging and non-invasive magnetic resonance spectroscopy methodologies. In addition to these clinical/translational research projects and the PGIC, the Harvard/Stanford GTN offers to host a Network Coordinating Center (NCC) for the broader GTN initiative (as described and specified by the FOA). Our proposed NCC offers essential skill sets in neuropathology, cancer genetics, clinical trials, biostatistics, and clinical trial design that will enable multiple GTN centers to work together in ways that exceed the sum of their component parts. An Administrative Core will serve as the primary contact and communication resource for the Projects, the PGIC, an Internal Advisory Board, the NCC, the GTN Steering Committee, and NCI program officials. The Harvard/Stanford GTN Principal Investigator is Tracy Batchelor, M.D. an experienced clinical trialist with much practical experience in leading large, multi- investigator/multi-institutional initiatives.

我们在此回应一项供多机构团队组成的资助机会公告 (FOA) 胶质母细胞瘤治疗网络 (GTN) 来自三位基础科学家和临床/转化研究人员。 丹娜—法伯癌症研究所/哈佛大学癌症中心 (DF/HCC) 的机构与其盟友联手， 斯坦福大学癌症中心 (SCC) 创建“哈佛/斯坦福大学 GTN”也是如此。 这一跨海岸 GTN 的一项重要合作特点包括 (i) 广泛而深入。 在脑渗透、小分子治疗方面的专业知识以及（ii）在新兴领域的强大影响力 癌症神经科学——研究神经系统在胶质母细胞瘤中的核心作用的领域 我们的目标是改善成人胶质母细胞瘤 (GBM) 和星形细胞瘤、IDH-的治疗。 突变体，4级，通过先导优化服用新型、有效、脑渗透性小分子药物， 我们的研究计划包括三个项目： 项目 1 的目标是星形细胞瘤、IDH 突变体、4 级的代谢重编程。项目 2 的目标是 在超过 50% 的成人 IDH 野生型 GBM 中观察到组成型、配体独立的 EGFR 信号传导。 项目 3 的目标是最近认识到肿瘤细胞和电之间的前馈神经胶质瘤形成环路 IDH 野生型成人胶质母细胞瘤中的活性神经元 所有三个项目均以手术窗口临床试验为特色。 迄今为止尚未在 GBM 中进行测试的脑渗透药物 此外，项目 2 将开发新型变构药物。 有望解决目前所有 EGFR 拮抗剂作为 GBM 治疗药物的缺点的抑制剂 - 也就是说， 缺乏治疗窗口将通过药理学和临床试验得到增强。 基因组成像核心 (PGIC)。该核心将使我们的试验人员能够监测药物对胶质母细胞瘤细胞的影响。 使用专门的单细胞 RNAseq 方案检测肿瘤内的药物外显率和药物诱导的人群。 使用基质辅助激光解吸电离质量可以可视化关键代谢物的变化 光谱成像和非侵入性磁共振光谱方法。 除了这些临床/转化研究项目和 PGIC 之外，哈佛/斯坦福 GTN 提议为更广泛的 GTN 计划主办一个网络协调中心 (NCC)（如所述和 由 FOA 指定）。我们提议的 NCC 提供神经病理学、癌症遗传学、 临床试验、生物统计学和临床​​试验设计，使多个 GTN 中心能够在 管理核心将作为主要联系人。 项目、PGIC、内部顾问委员会、NCC、GTN 的沟通资源 指导委员会和 NCI 项目官员 哈佛/斯坦福 GTN 首席研究员是 Tracy。 Batchelor 医学博士是一位经验丰富的临床试验师，在领导大型、多中心临床试验方面拥有丰富的实践经验。 研究者/多机构倡议。