Targeting metabolic vulnerabilities in Astrocytoma, IDH-mutant, Grade 4

针对星形细胞瘤、IDH 突变、4 级的代谢脆弱性

基本信息

  • 批准号:
    10306229
  • 负责人:
  • 金额:
    $ 19.5万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 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

项目摘要

PROJECT SUMMARY Gliomas represent 80% of the 26,000 newly diagnosed cases of malignant brain and central nervous system tumors in the United States each year and are among the most lethal and treatment-resistant human cancers. Although there is a dire need for effective therapies for this disease, the standard treatment for gliomas has not changed since 2005 and no new medical therapies have been approved for adult gliomas in the last decade. In response to this challenge, we have devised a new way to treat gliomas that have a mutation in either of the IDH1 or IDH2 genes. Collectively, IDH mutations are present in ~20% of adult diffuse gliomas, indicating that any treatment advance in this patient population would have broad impact. Based on our knowledge that IDH mutations cause profound metabolic reprogramming in glioma cells, we used a novel pharmacological screening platform to systematically identify vulnerabilities that result from this process. We discovered that a class of drugs targeting nucleotide metabolism preferentially kill glioma cells with IDH mutations, thereby revealing an avenue for tumor-selective, biomarker-guided therapy that is poised for rapid clinical translation. To build on this discovery and translate exploitation of this vulnerability to the clinic, we propose to conduct a phase 0 surgical window clinical trial of a brain-penetrant nucleotide metabolism inhibitor in IDH-mutant grade 4 glioma patients. We will characterize response to this agent by addressing three Specific Aims. Specific Aim #1 is to use matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI), conventional liquid chromatography-mass spectrometry, and magnetic resonance spectroscopy to comprehensively characterize the pharmacokinetic and pharmacodynamic properties of this targeted therapeutic in glioma patients. Specific Aim #2 is to investigate how this inhibitor alters the biology of IDH-mutant grade 4 gliomas at the molecular and cellular levels by analyzing resected primary tissue samples via single-cell RNA sequencing and immunohistochemistry. Finally, Specific Aim #3 is to evaluate the safety and tolerability of this drug in a focused cohort of IDH-mutant grade 4 glioma patients. Taken together, our work will outline and test a new treatment strategy for glioma patients that could be expanded to a larger multi-center phase II study if our trial is successful. Furthermore, our efforts to elucidate key components of the mechanism of action of this nucleotide metabolism inhibitor are expected to inform the rational design of combination therapies centered on this agent that can be explored in future studies.
项目摘要 神经胶质瘤占26,000例新诊断的脑和中枢神经系统恶性病例的80% 在美国每年发生的恶性肿瘤,是最致命和最难治疗的人类癌症之一。 尽管对这种疾病的有效疗法存在迫切需求,但神经胶质瘤的标准治疗还没有 自2005年以来,神经胶质瘤的治疗方法发生了变化,在过去的十年中,没有新的药物治疗方法被批准用于成人神经胶质瘤。在 为了应对这一挑战,我们设计了一种新的方法来治疗神经胶质瘤, IDH 1或IDH 2基因。总的来说,IDH突变存在于约20%的成人弥漫性胶质瘤中,表明 在这一患者群体中的任何治疗进展都将具有广泛的影响。根据我们对IDH的了解, 突变会导致胶质瘤细胞发生深刻的代谢重编程,我们使用了一种新型药理学方法 筛选平台,以系统地确定从这一过程中产生的漏洞。我们发现, 一类靶向核苷酸代谢的药物优先杀死具有IDH突变的胶质瘤细胞, 揭示了一种肿瘤选择性、生物标志物引导的治疗方法,有望快速临床转化。 为了建立在这一发现的基础上,并将这一漏洞的利用转化为临床,我们建议进行一次 脑渗透性核苷酸代谢抑制剂在IDH突变分级中的0期手术窗临床试验 胶质瘤4例。我们将通过解决三个具体目标来描述对这种药物的反应。具体目标 #1是使用基质辅助激光解吸电离质谱成像(MALDI-MSI),常规 液相色谱-质谱法和磁共振光谱法, 描述这种靶向治疗药物在胶质瘤中的药代动力学和药效学特性 患者具体目标#2是研究这种抑制剂如何改变IDH突变型4级胶质瘤的生物学, 通过单细胞RNA测序分析切除的原代组织样本, 和免疫组织最后,具体目标#3是评估该药物在一个受试者中的安全性和耐受性。 IDH突变型4级胶质瘤患者的集中队列。总之,我们的工作将概述和测试一个新的 胶质瘤患者的治疗策略,可以扩展到一个更大的多中心II期研究,如果我们的试验 是成功的此外,我们努力阐明这种作用机制的关键组成部分, 核苷酸代谢抑制剂,预计将告知联合治疗的合理设计, 可以在未来的研究中探索。

项目成果

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Tracy T Batchelor其他文献

Correcting the drug development paradigm for glioblastoma requires serial tissue sampling
纠正胶质母细胞瘤的药物开发范式需要连续组织采样
  • DOI:
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Kirit Singh;K. Hotchkiss;I. Parney;J. D. de Groot;S. Sahebjam;N. Sanai;M. Plattén;E. Galanis;Michael Lim;P. Wen;G. Minniti;H. Colman;T. Cloughesy;M. Mehta;M. Geurts;I. Arrillaga;A. Desjardins;K. Tanner;S. Short;David F. Arons;Elizabeth S Duke;W. Wick;S. Bagley;D. Ashley;P. Kumthekar;R. Verhaak;A. Chalmers;Anoop P. Patel;Colin Watts;P. Fecci;Tracy T Batchelor;M. Weller;M. Vogelbaum;M. Preusser;Mitchel S. Berger;M. Khasraw
  • 通讯作者:
    M. Khasraw
Association of MTHFR Polymorphisms With Leukoencephalopathy Risk in Patients With Primary CNS Lymphoma Treated With Methotrexate-Based Regimens
MTHFR 多态性与接受甲氨蝶呤方案治疗的原发性中枢神经系统淋巴瘤患者白质脑病风险的关联
  • DOI:
    10.1212/wnl.0000000000207670
  • 发表时间:
    2023
  • 期刊:
  • 影响因子:
    9.9
  • 作者:
    P. Karschnia;Sylvia C. Kurz;P. Brastianos;Sebastian F. Winter;A. Gordon;SooAe Jones;M. Pisapia;Naema Nayyar;J. Tonn;Tracy T Batchelor;S. Plotkin;J. Dietrich
  • 通讯作者:
    J. Dietrich

Tracy T Batchelor的其他文献

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{{ truncateString('Tracy T Batchelor', 18)}}的其他基金

Cancer Neuroscience Training Program
癌症神经科学培训计划
  • 批准号:
    10714321
  • 财政年份:
    2023
  • 资助金额:
    $ 19.5万
  • 项目类别:
Project-008
项目-008
  • 批准号:
    10710260
  • 财政年份:
    2022
  • 资助金额:
    $ 19.5万
  • 项目类别:
Project-007
项目-007
  • 批准号:
    10710259
  • 财政年份:
    2022
  • 资助金额:
    $ 19.5万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 19.5万
  • 项目类别:
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
  • 财政年份:
    2021
  • 资助金额:
    $ 19.5万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10306227
  • 财政年份:
    2021
  • 资助金额:
    $ 19.5万
  • 项目类别:
Annual Meeting of the International Primary CNS Lymphoma Collaborative Group (IPCG)
国际原发性中枢神经系统淋巴瘤协作组(IPCG)年会
  • 批准号:
    10391991
  • 财政年份:
    2021
  • 资助金额:
    $ 19.5万
  • 项目类别:
Targeting metabolic vulnerabilities in Astrocytoma, IDH-mutant, Grade 4
针对星形细胞瘤、IDH 突变、4 级的代谢脆弱性
  • 批准号:
    10491830
  • 财政年份:
    2021
  • 资助金额:
    $ 19.5万
  • 项目类别:
Administrative Core
行政核心
  • 批准号:
    10491820
  • 财政年份:
    2021
  • 资助金额:
    $ 19.5万
  • 项目类别:
Career Development Research Project
职业发展研究项目
  • 批准号:
    9365925
  • 财政年份:
    2016
  • 资助金额:
    $ 19.5万
  • 项目类别:

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