Harvard/Stanford GTN Program: Novel targeted therapeutics for glioblastoma

我们在这里回应一个资金机会公告（FOA），为多机构的团队，以形成一个 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/转化研究人员 丹娜-法伯/哈佛癌症中心（DF/HCC）的机构已经与他们的同行联手， 斯坦福大学癌症中心（SCC）创建“哈佛/斯坦福大学GTN”。西南大学也是 在一个关键的合作。这个双海岸GTN的显著特征包括：（i）宽而深， 在脑渗透，小分子治疗的专业知识和（ii）在新兴领域的强大存在， 癌症神经科学-解决神经系统在胶质母细胞瘤中的核心作用的领域 发病机制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级通过服用新型，有效，脑渗透小分子药物，通过铅优化， 临床前开发和早期临床试验。我们的学习计划包括三个项目： 项目1针对星形细胞瘤，IDH突变体，4级的代谢重编程。项目2的目标是 在超过50%的成年IDH野生型GBM中观察到组成型、配体非依赖性EGFR信号传导。 项目3的目标是肿瘤细胞之间的一个最近受到赞赏的前馈神经胶质瘤环， IDH野生型成人胶质母细胞瘤中的活性神经元。这三个项目都有手术窗临床试验， 迄今为止尚未在GBM中测试的脑渗透药物。此外，项目2将开发新的变构 有望解决目前所有EGFR拮抗剂作为GBM治疗剂的缺点的抑制剂-即， 缺乏治疗窗口。从临床试验的见解将加强药理学和 基因组成像核心（PGIC）。这个核心将允许我们的试验人员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方案对群体进行测序。肿瘤内药物转运和药物诱导 将使用基质辅助激光解吸电离质谱观察关键代谢物的变化 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，哈佛/斯坦福大学GTN 提出为更广泛的GTN倡议（如所述）主办网络协调中心（NCC）， 由FOA指定）。我们建议的NCC提供神经病理学，癌症遗传学， 临床试验、生物统计学和临床试验设计，使多个GTN中心能够共同工作， 超过其组成部分之和的方式。行政核心将作为主要联系人 项目、PGIC、内部咨询委员会、NCC、GTN的沟通资源 指导委员会和NCI项目官员。哈佛/斯坦福大学GTN首席研究员是Tracy Batchelor，医学博士一位经验丰富的临床试验专家，在领导大型、多中心、 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.