Targeting metabolic vulnerabilities induced by the 1p19q codeletion in oligodendrogliomas

针对少突胶质细胞瘤中 1p19q 编码缺失引起的代谢脆弱性

基本信息

项目摘要

PROJECT SUMMARY Gliomas are the most common malignant primary brain tumors in adults. Among gliomas driven by mutant isocitrate dehydrogenase, tumors harboring a 1p/19q codeletion are classified as oligodendrogliomas. Current therapies such as radiation and chemotherapy are highly toxic and cause long-lasting and life-altering deficits in cognitive and physical abilities. Importantly, although oligodendroglioma patients live for years with standard treatment, tumors inevitably recur and cause patient death. Since the 1p/19q codeletion is a hallmark of oligodendrogliomas, identifying metabolic vulnerabilities associated with the 1p/19 codeletion can lead to precision medicines for oligodendroglioma patients. Glycolytic metabolism, in particular, fuels biosynthesis and bioenergetics and is central to tumor proliferation. The glycolytic gene enolase 1, which is located on chromosome 1p36.23, is lost in oligodendrogliomas due to the 1p/19q codeletion, leaving these tumors dependent on enolase 2 (ENO2) for continued glycolysis. Our studies indicate that inhibiting ENO2 using a safe, potent ENO2 inhibitor (POMHEX) downregulates glycolysis in patient-derived oligodendrogliomas. However, ENO2 inhibition leads to a compensatory activation of pyruvate dehydrogenase (PDH), a key tricarboxylic acid (TCA) cycle enzyme. Importantly, combining POMHEX with the novel safe PDH inhibitor CPI- 613 completely abrogates glycolysis, the TCA cycle and oligodendroglioma growth. We will, therefore, test the hypothesis that targeting ENO2 and PDH is a precision therapy strategy for oligodendrogliomas (Aim 1). Successful translation of novel therapies is hindered by the lack of companion biomarkers that report on response to therapy. Magnetic resonance imaging, which is the mainstay of glioma imaging, fails to accurately report on response to therapy. Deuterium Magnetic Resonance Spectroscopy (DMRS) following administration of 2H-labeled substrates such as glucose is a safe clinically translatable method of imaging glycolytic flux in vivo. In Aim 2, we will examine the ability of 2H-glucose to report on response to ENO2 and PDH inhibition in oligodendrogliomas in vivo at clinically relevant field strength (3T). Our proposal is innovative and impactful because it will validate ENO2 and PDH as precision targets for oligodendrogliomas in this era of genomic medicine. Since the safety of POMHEX and CPI-613 has been established in primates and humans, and since DMRS can be readily deployed on clinical MR scanners, our therapies and companion biomarkers have the potential to be rapidly translated to the clinic. In essence, by simultaneously targeting metabolism for therapy and for imaging treatment response, our studies will enable precision medicine that improves outcomes and quality of life for oligodendroglioma patients.
项目摘要 胶质瘤是成人最常见的恶性原发性脑肿瘤。在由突变基因驱动的胶质瘤中, 异柠檬酸脱氢酶,携带1 p/19 q共缺失的肿瘤被分类为少突胶质细胞瘤。电流 放疗和化疗等治疗具有高毒性,会导致长期和改变生命的缺陷 在认知和身体能力方面。重要的是,尽管少突胶质细胞瘤患者在标准的 治疗时,肿瘤不可避免地复发并导致患者死亡。由于1 p/19 q共缺失是 少突胶质细胞瘤,识别与1 p/19共缺失相关的代谢脆弱性可导致 为少突胶质细胞瘤患者提供精准药物。糖酵解代谢,特别是燃料生物合成和 生物能量学和肿瘤增殖的核心。糖酵解基因烯醇化酶1位于 染色体1p36.23在少突胶质细胞瘤中由于1 p/19 q共缺失而丢失, 依赖烯醇化酶2(ENO 2)继续糖酵解。我们的研究表明,抑制ENO 2使用 安全有效的ENO 2抑制剂(POMHEX)下调患者来源的少突胶质细胞瘤中的糖酵解。 然而,ENO 2抑制导致丙酮酸脱氢酶(PDH)的代偿性激活,这是一个关键因素。 三羧酸(TCA)循环酶。重要的是,将POMHEX与新型安全的PDH抑制剂CPI- 613完全消除糖酵解、TCA循环和少突胶质细胞瘤生长。因此,我们将测试 假设靶向ENO 2和PDH是少突胶质细胞瘤的精确治疗策略(目的1)。 新疗法的成功转化受到缺乏报告以下方面的伴随生物标志物的阻碍: 对治疗的反应。磁共振成像,这是神经胶质瘤成像的支柱,未能准确地 报告治疗反应。给药后的氘磁共振光谱(DMRS) 2 H标记底物如葡萄糖是一种安全的临床上可翻译的成像糖酵解通量的方法, vivo.在目的2中,我们将检查2 H-葡萄糖报告对EN 02和PDH抑制的响应的能力, 在临床相关的场强(3 T)下,体内的少突胶质细胞瘤。 我们的建议是创新和有影响力的,因为它将验证ENO 2和PDH作为精确目标, 少突胶质细胞瘤在这个基因组医学时代。由于POMHEX和CPI-613的安全性已被 在灵长类动物和人类中建立,并且由于DMRS可以很容易地部署在临床MR扫描仪上, 治疗和伴随生物标志物具有快速转化为临床的潜力。从本质上讲, 同时靶向代谢治疗和成像治疗反应,我们的研究将使 精准医疗,改善少突胶质细胞瘤患者的预后和生活质量。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Pavithra Viswanath其他文献

Pavithra Viswanath的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

相似国自然基金

甲基化沉默的新1p36抑癌基因TUSC6在鼻咽癌和结直肠癌中的功能和分子机制研究
  • 批准号:
    81301783
  • 批准年份:
    2013
  • 资助金额:
    23.0 万元
  • 项目类别:
    青年科学基金项目

相似海外基金

Identifying and targeting collateral lethal vulnerabilities in cancers
识别并针对癌症的附带致命弱点
  • 批准号:
    10563469
  • 财政年份:
    2023
  • 资助金额:
    $ 18.88万
  • 项目类别:
Probing INTS11 as a novel target in neuroblastoma
探索 INTS11 作为神经母细胞瘤的新靶点
  • 批准号:
    10577214
  • 财政年份:
    2023
  • 资助金额:
    $ 18.88万
  • 项目类别:
Characterization of DHDDS RP59 Knockin Models of Retinitis Pigmentosa
视网膜色素变性 DHDDS RP59 敲入模型的表征
  • 批准号:
    10507785
  • 财政年份:
    2021
  • 资助金额:
    $ 18.88万
  • 项目类别:
Characterization of DHDDS RP59 Knockin Models of Retinitis Pigmentosa
视网膜色素变性 DHDDS RP59 敲入模型的表征
  • 批准号:
    10232038
  • 财政年份:
    2021
  • 资助金额:
    $ 18.88万
  • 项目类别:
Pro-Drug Enolase Inhibitors in Precision Oncology
精准肿瘤学中的前药烯醇化酶抑制剂
  • 批准号:
    10560633
  • 财政年份:
    2021
  • 资助金额:
    $ 18.88万
  • 项目类别:
Pro-Drug Enolase Inhibitors in Precision Oncology
精准肿瘤学中的前药烯醇化酶抑制剂
  • 批准号:
    10347363
  • 财政年份:
    2021
  • 资助金额:
    $ 18.88万
  • 项目类别:
Characterization of DHDDS RP59 Knockin Models of Retinitis Pigmentosa
视网膜色素变性 DHDDS RP59 敲入模型的表征
  • 批准号:
    10571927
  • 财政年份:
    2021
  • 资助金额:
    $ 18.88万
  • 项目类别:
PRDM16 in cardiac development
PRDM16 在心脏发育中的作用
  • 批准号:
    10025986
  • 财政年份:
    2020
  • 资助金额:
    $ 18.88万
  • 项目类别:
The Role of PRDM16 in Cardiac Development and Cardiomyopathy
PRDM16 在心脏发育和心肌病中的作用
  • 批准号:
    10627955
  • 财政年份:
    2020
  • 资助金额:
    $ 18.88万
  • 项目类别:
PRDM16 in cardiac development
PRDM16 在心脏发育中的作用
  • 批准号:
    10242912
  • 财政年份:
    2020
  • 资助金额:
    $ 18.88万
  • 项目类别:
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了