Harvard/Stanford GTN Program: Novel targeted therapeutics for glioblastoma

我们在这里回应多机构团队的融资机会公告(FOA)，以形成 胶质母细胞瘤治疗网络(GTN)。来自三个国家的基础科学家和临床/翻译研究人员 达纳-法伯/哈佛癌症中心(DF/HCC)的机构与他们的同行在 斯坦福大学癌症中心(SCC)创建了“哈佛/斯坦福GTN”。德克萨斯大学西南分校也是 在一个关键的协作中得到代表。这一两个沿海地区GTN的显著特征包括：(1)广度和深度 在脑渗透、小分子疗法方面的专业知识以及(Ii)在新兴领域的强大影响力 肿瘤神经科学--研究神经系统在胶质母细胞瘤中的中心作用的领域 发病机制。我们的目标是提高成人胶质母细胞瘤和星形细胞瘤的治疗水平。 突变体，4级，通过先导优化服用新颖、有效、透脑的小分子药物，以 临床前开发和进入早期临床试验。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的代谢重新编程，IDH突变，4级。项目2的目标是 在超过50%的成人IDH野生型GBM中观察到构成的、非配体依赖的EGFR信号。 项目3的目标是最近得到认可的肿瘤细胞之间的前馈神经胶质瘤环路和电信号 IDH野生型成人胶质母细胞瘤中的活跃神经元。这三个项目都以外科窗口临床试验为特色 到目前为止还没有在GBM中测试的脑穿透药物。此外，项目2还将开发新型变构 承诺解决目前所有EGFR拮抗剂作为GBM疗法的缺点的抑制剂-换句话说， 缺乏一个治疗的窗口。临床试验的洞察力将通过一种药理学和 基因组成像核心(PGIC)。这一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协议的种群。药物在肿瘤内的穿透性与药物诱导 主要代谢物的变化将使用基质辅助激光解吸电离质量来可视化 光谱成像和非侵入性磁共振波谱方法学。 除了这些临床/转化性研究项目和PGIC，哈佛/斯坦福大学GTN 提议为更广泛的GTN计划主办网络协调中心(NCC)(如上所述，并 由《外国投资协定》规定)。我们建议的NCC提供神经病理学、癌症遗传学、 临床试验、生物统计和临床试验设计，使多个GTN中心能够在 超过其组成部分之和的方法。行政核心将作为主要联系人 项目、PGIC、内部咨询委员会、NCC、GTN的信息和通信资源 指导委员会和NCI项目官员。哈佛/斯坦福GTN首席研究员是特雷西 Batchelor医学博士是一位经验丰富的临床试验人员，在领导大型、多领域的 调查员/多机构倡议。

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.