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: 10306226
• 负责人: Tracy T Batchelor
• 金额: $ 101.45万
• 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/10306226
• 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; base; cancer genetics; cancer imaging; cell type; clinical efficacy; clinical material; cost effective; early phase clinical trial; experience; feeding; imaging facilities; improved; inhibitor/antagonist; insight; lead optimization; 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.

我们在这里回应了一项资金机会公告（FOA），以供多机构的团队组成 胶质母细胞瘤治疗网络（GTN）。来自三个的基础科学家和临床/翻译调查员 Dana-Farber/Harvard Cancer Center（DF/HCC）的机构已与他们的同行一起 斯坦福癌症中心（SCC）创建“哈佛/斯坦福GTN”。 UT西南也是 在一个关键的合作中代表。该双层GTN的独特特征包括（i）宽而深 在脑培训，小分子疗法和（ii）在新兴领域的强大存在方面的专业知识 癌症神经科学 - 一个针对神经系统在胶质母细胞瘤中的中心作用的领域 发病。我们的目标是改善成人胶质母细胞瘤（GBM）和星形胶质细胞瘤的治疗，IDH- 突变体，4级，通过通过铅优化服用新颖，有效的脑培训小分子药物， 临床前开发并进入早期临床试验。我们的学习计划特征了三个项目： 项目1靶向星形胶质细胞瘤的代谢重编程，IDH突变体，4年级。项目2针对 在超过50％的成年IDH野生型GBM中观察到组成型，独立的EGFR信号传导。 项目3的目标是最近对肿瘤细胞之间的前馈胶质素环路和电气的吸引力的目标。 IDH野生型成人胶质母细胞瘤中的活性神经元。这三个项目均采用外科窗口临床试验 在GBM中未经测试的脑培养剂药物。此外，项目2将发展出新颖的变构 有望解决所有当前EGFR拮抗剂作为GBM治疗的抑制剂 - 机智， 缺乏治疗窗口。临床试验的见解将通过药理学和 基因组成像核（PGIC）。该核心将使我们的试验者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方案的种群。肿瘤中的药物渗透和药物诱导的 将使用基质辅助激光解吸电离质量来可视化关键代谢产物的变化 光谱成像和非侵入性磁共振光谱法。 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计划主持网络协调中心（NCC）（如所述和 由FOA指定）。我们提出的NCC提供了神经病理学，癌症遗传学的基本技能， 临床试验，生物统计学和临床​​试验设计将使多个GTN中心共同工作 超过其组件部分总和的方式。行政核心将作为主要联系 和项目的通信资源，PGIC，内部顾问委员会，NCC，GTN 指导委员会和NCI计划官员。哈佛/斯坦福GTN首席研究员是特雷西 Batchelor，医学博士，一位经验丰富的临床试验师 研究人员/多机构倡议。