Metabolic Reprogramming in Brain Tumors

脑肿瘤的代谢重编程

基本信息

项目摘要

ABSTRACT The goal of this competitive renewal is to identify and validate novel translatable metabolic imaging biomarkers of response to advanced clinically-relevant therapies that target isocitrate dehydrogenase 1 (IDH1) in the treatment of mutant IDH1 glioma. The IDH1 mutation is a `driver mutation' that is present in 70-90% of low- grade glioma and secondary upgraded glioblastoma. In an effort to improve the treatment of mutant IDH1 tumors, novel therapeutic approaches are been developed, and data shows that siRNA targeting both wild-type (wt) and mutant IDH1, as well as new dual (wt/mutant) IDH inhibitors now in clinical trials, lead to a clear response. However, no noninvasive imaging methods are available to assess drug-target engagement or predict response. During the first funding period of this grant we identified several mutant IDH1-driven 1H magnetic resonance spectroscopy (MRS)-detectable metabolic alterations, and developed novel translational hyperpolarized 13C MRS-based imaging approaches that inform on the presence of the mutation. Our preliminary data indicate that response to treatment with emerging dual inhibitors is associated with a reversal of all the 1H MRS-detectable metabolic alterations observed in mutant cells but not with all of the associated hyperpolarized 13C MRS-detectable metabolic fluxes, likely reflecting inhibition of wt IDH1. In addition, levels of glutathione (GSH) and the ratio of GSH to its oxidized form GSSG drop, pointing to additional imageable metabolic reactions associated with response. We therefore hypothesize that using some of our previously identified MRS biomarkers of mutant IDH1, as well as imaging biomarkers of redox status, it will be possible to monitor the therapeutic effects of dual IDH inhibitors that are entering the clinic. Aim 1. To identify 1H and hyperpolarized 13C MRS-detectable metabolic biomarkers associated with response to novel IDH-targeting therapies in mutant IDH1 cells. We will investigate genetically-engineered and patient-derived cell models, and use 1H and hyperpolarized 13C MRS to identify the imageable metabolic alterations that are uniquely associated with response to therapy as determined by inhibition in cell proliferation and/or clonogenic potential. Aim 2. To mechanistically validate 1H and hyperpolarized 13C MRS imaging biomarkers of response. We will use a range of biochemical, cell, and molecular biological assays as well as specific inhibitors to determine the mechanistic link between drug action and the metabolic imaging biomarkers identified in Aim 1. Aim 3. To confirm in vivo the 1H and hyperpolarized 13C MRS metabolic imaging biomarkers as indicators of tumor response to novel IDH-targeting therapies in mutant IDH1 tumors. We will treat tumor-bearing mice, and use MRI with 1H and hyperpolarized 13C MRSI, to longitudinally monitor the effect of therapy on tumor growth and metabolism, and assess the value of our metabolic imaging biomarkers for prediction of response as assessed by tumor size and/or animal survival.
摘要 这一竞争性更新的目标是确定和验证新的可翻译的代谢成像生物标志物 对靶向异柠檬酸脱氢酶1(IDH 1)的高级临床相关疗法的反应 突变IDH 1胶质瘤的治疗。IDH 1突变是一种“驱动突变”,存在于70-90%的低血糖患者中。 级胶质瘤和继发性升级的胶质母细胞瘤。为了改善突变IDH 1的治疗, 在肿瘤中,新的治疗方法被开发出来,数据显示,靶向野生型和非野生型的siRNA都可以用于治疗肿瘤。 (wt)和突变IDH 1,以及新的双重(野生型/突变型)IDH抑制剂,现在在临床试验中,导致一个明确的 反应然而,没有非侵入性成像方法可用于评估药物-靶点接合或靶向治疗。 预测响应。在这项资助的第一个资助期内,我们发现了几个突变的IDH 1驱动的1H 磁共振波谱(MRS)检测代谢改变,并开发了新的翻译 基于超极化13 C MRS的成像方法,其告知突变的存在。我们 初步数据表明,对新出现的双重抑制剂治疗的反应与逆转有关, 在突变细胞中观察到的所有1H MRS可检测的代谢改变中, 超极化的13 C MRS可检测的代谢通量,可能反映了wt IDH 1的抑制。此外, 谷胱甘肽(GSH)和GSH与其氧化形式GSSG的比率下降,指向额外的成像 与反应相关的代谢反应。因此,我们假设,使用我们以前的一些 鉴定的突变IDH 1的MRS生物标志物,以及氧化还原状态的成像生物标志物, 监测正在进入临床的双重IDH抑制剂的治疗效果。 目标1。鉴定与以下相关的1H和超极化13 C MRS可检测的代谢生物标志物: 在突变IDH 1细胞中对新型IDH靶向疗法的反应。我们将研究基因工程 和患者来源的细胞模型,并使用1H和超极化13 C MRS来鉴定可成像的代谢产物。 通过抑制细胞增殖确定的与治疗反应唯一相关的改变 和/或克隆形成潜力。 目标二。从机制上验证反应的1H和超极化13 C MRS成像生物标志物。我们 将使用一系列生物化学,细胞和分子生物学检测以及特定的抑制剂来确定 药物作用与目标1中确定的代谢成像生物标志物之间的机制联系。 目标3。为了在体内证实1H和超极化13 C MRS代谢成像生物标志物, 突变IDH 1肿瘤中对新型IDH靶向治疗的肿瘤反应指标。本公司对待 荷瘤小鼠,并使用MRI与1H和超极化13 C MRSI,纵向监测的影响, 肿瘤生长和代谢的治疗,并评估我们的代谢成像生物标志物的价值, 通过肿瘤大小和/或动物存活率评估的反应预测。

项目成果

期刊论文数量(21)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Glioma cells with the IDH1 mutation modulate metabolic fractional flux through pyruvate carboxylase.
具有IDH1突变的胶质瘤细胞通过丙酮酸羧化酶调节代谢分数通量。
  • DOI:
    10.1371/journal.pone.0108289
  • 发表时间:
    2014
  • 期刊:
  • 影响因子:
    3.7
  • 作者:
    Izquierdo-Garcia JL;Cai LM;Chaumeil MM;Eriksson P;Robinson AE;Pieper RO;Phillips JJ;Ronen SM
  • 通讯作者:
    Ronen SM
In vivo metabolic imaging of Traumatic Brain Injury.
  • DOI:
    10.1038/s41598-017-17758-4
  • 发表时间:
    2017-12-13
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Guglielmetti C;Chou A;Krukowski K;Najac C;Feng X;Riparip LK;Rosi S;Chaumeil MM
  • 通讯作者:
    Chaumeil MM
Glutamate Is a Noninvasive Metabolic Biomarker of IDH1-Mutant Glioma Response to Temozolomide Treatment.
  • DOI:
    10.1158/0008-5472.can-20-1314
  • 发表时间:
    2020-11-15
  • 期刊:
  • 影响因子:
    11.2
  • 作者:
    Subramani E;Radoul M;Najac C;Batsios G;Molloy AR;Hong D;Gillespie AM;Santos RD;Viswanath P;Costello JF;Pieper RO;Ronen SM
  • 通讯作者:
    Ronen SM
Detection of inflammatory cell function using (13)C magnetic resonance spectroscopy of hyperpolarized [6-(13)C]-arginine.
使用超极化 [6-(13)C]-精氨酸的 (13)C 磁共振波谱检测炎症细胞功能。
  • DOI:
    10.1038/srep31397
  • 发表时间:
    2016
  • 期刊:
  • 影响因子:
    4.6
  • 作者:
    Najac,Chloé;Chaumeil,MyriamM;Kohanbash,Gary;Guglielmetti,Caroline;Gordon,JeremyW;Okada,Hideho;Ronen,SabrinaM
  • 通讯作者:
    Ronen,SabrinaM
Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters.
  • DOI:
    10.18632/oncotarget.9006
  • 发表时间:
    2016-06-07
  • 期刊:
  • 影响因子:
    0
  • 作者:
    Viswanath P;Najac C;Izquierdo-Garcia JL;Pankov A;Hong C;Eriksson P;Costello JF;Pieper RO;Ronen SM
  • 通讯作者:
    Ronen SM
{{ 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 }}

Sabrina Miriam Ronen其他文献

Sabrina Miriam Ronen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 }}

{{ truncateString('Sabrina Miriam Ronen', 18)}}的其他基金

IMAGING TELOMERE MAINTENANCE MECHANISMS IN GLIOMAS
胶质瘤中端粒维持机制的成像
  • 批准号:
    10328937
  • 财政年份:
    2020
  • 资助金额:
    $ 63.7万
  • 项目类别:
IMAGING TELOMERE MAINTENANCE MECHANISMS IN GLIOMAS
胶质瘤中端粒维持机制的成像
  • 批准号:
    10552020
  • 财政年份:
    2020
  • 资助金额:
    $ 63.7万
  • 项目类别:
IMAGING TELOMERE MAINTENANCE MECHANISMS IN GLIOMAS
胶质瘤中端粒维持机制的成像
  • 批准号:
    9905433
  • 财政年份:
    2020
  • 资助金额:
    $ 63.7万
  • 项目类别:
Metabolic Imaging of Brain Tumor Response to Therapy
脑肿瘤治疗反应的代谢成像
  • 批准号:
    9249001
  • 财政年份:
    2016
  • 资助金额:
    $ 63.7万
  • 项目类别:
Metabolic Reprogramming in Brain Tumors
脑肿瘤的代谢重编程
  • 批准号:
    8613480
  • 财政年份:
    2013
  • 资助金额:
    $ 63.7万
  • 项目类别:
Metabolic Reprogramming in Brain Tumors
脑肿瘤的代谢重编程
  • 批准号:
    8421781
  • 财政年份:
    2013
  • 资助金额:
    $ 63.7万
  • 项目类别:
Metabolic Reprogramming in Brain Tumors
脑肿瘤的代谢重编程
  • 批准号:
    9204396
  • 财政年份:
    2013
  • 资助金额:
    $ 63.7万
  • 项目类别:
MR Imaging of IDH Mutational Status in Brain Tumors
脑肿瘤 IDH 突变状态的 MR 成像
  • 批准号:
    8299794
  • 财政年份:
    2012
  • 资助金额:
    $ 63.7万
  • 项目类别:
MR Imaging of IDH Mutational Status in Brain Tumors
脑肿瘤 IDH 突变状态的 MR 成像
  • 批准号:
    8452079
  • 财政年份:
    2012
  • 资助金额:
    $ 63.7万
  • 项目类别:
Phosphocholine modulation by oncognenic signaling - MRS studies of mechanism
致癌信号传导的磷酸胆碱调节 - MRS 机制研究
  • 批准号:
    7923182
  • 财政年份:
    2008
  • 资助金额:
    $ 63.7万
  • 项目类别:

相似海外基金

CAREER: Biochemical and Structural Mechanisms Controlling tRNA-Modifying Metalloenzymes
职业:控制 tRNA 修饰金属酶的生化和结构机制
  • 批准号:
    2339759
  • 财政年份:
    2024
  • 资助金额:
    $ 63.7万
  • 项目类别:
    Continuing Grant
Systematic manipulation of tau protein aggregation: bridging biochemical and pathological properties
tau 蛋白聚集的系统操作:桥接生化和病理特性
  • 批准号:
    479334
  • 财政年份:
    2023
  • 资助金额:
    $ 63.7万
  • 项目类别:
    Operating Grants
Diurnal environmental adaptation via circadian transcriptional control based on a biochemical oscillator
基于生化振荡器的昼夜节律转录控制的昼夜环境适应
  • 批准号:
    23H02481
  • 财政年份:
    2023
  • 资助金额:
    $ 63.7万
  • 项目类别:
    Grant-in-Aid for Scientific Research (B)
Leveraging releasable aryl diazonium ions to probe biochemical systems
利用可释放的芳基重氮离子探测生化系统
  • 批准号:
    2320160
  • 财政年份:
    2023
  • 资助金额:
    $ 63.7万
  • 项目类别:
    Standard Grant
Biochemical Mechanisms for Sustained Humoral Immunity
持续体液免疫的生化机制
  • 批准号:
    10637251
  • 财政年份:
    2023
  • 资助金额:
    $ 63.7万
  • 项目类别:
Structural and biochemical investigations into the mechanism and evolution of soluble guanylate cyclase regulation
可溶性鸟苷酸环化酶调节机制和进化的结构和生化研究
  • 批准号:
    10604822
  • 财政年份:
    2023
  • 资助金额:
    $ 63.7万
  • 项目类别:
Enhanced Biochemical Monitoring for Aortic Aneurysm Disease
加强主动脉瘤疾病的生化监测
  • 批准号:
    10716621
  • 财政年份:
    2023
  • 资助金额:
    $ 63.7万
  • 项目类别:
Converting cytoskeletal forces into biochemical signals
将细胞骨架力转化为生化信号
  • 批准号:
    10655891
  • 财政年份:
    2023
  • 资助金额:
    $ 63.7万
  • 项目类别:
Chemical strategies to investigate biochemical crosstalk in human chromatin
研究人类染色质生化串扰的化学策略
  • 批准号:
    10621634
  • 财政年份:
    2023
  • 资助金额:
    $ 63.7万
  • 项目类别:
EAGER: Elastic Electronics for Sensing Gut Luminal and Serosal Biochemical Release
EAGER:用于感测肠腔和浆膜生化释放的弹性电子器件
  • 批准号:
    2334134
  • 财政年份:
    2023
  • 资助金额:
    $ 63.7万
  • 项目类别:
    Standard Grant
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了