Metabolic Reprogramming in Brain Tumors

脑肿瘤的代谢重编程

基本信息

批准号：
10348208
负责人：
Sabrina Miriam Ronen
金额：
$ 63.7万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-05 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10348208
关键词：
Animals Biochemical Biological Assay Biological Markers Brain Neoplasms Cell Proliferation Cell model Cells Clinic Clinical Research Clinical Trials Data Decarboxylation Development Drops Drug Targeting Event Funding Genes Genetic Engineering Glioblastoma Glioma Glutamates Glutathione Glutathione Disulfide Goals Grant Growth Image Isocitrate Dehydrogenase Isocitrates Lead Link Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Metabolic Metabolism Modeling Molecular Monitor Mus Mutation Outcome Oxidation-Reduction Oxides Patient Care Patients Pharmacologic Substance Phosphorylcholine Progress Reports Pyruvate Quality of life Reaction Research Role Small Interfering RNA Therapeutic Therapeutic Effect alpha ketoglutarate base clinically relevant driver mutation drug action imaging approach imaging biomarker imaging modality improved in vivo inhibitor innovation magnetic resonance spectroscopic imaging metabolic imaging mutant non-invasive imaging novel novel therapeutic intervention personalized care predicting response response response biomarker targeted treatment tool treatment optimization treatment response tumor tumor growth tumor metabolism

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.

抽象的此次竞争性更新的目标是识别和验证新型可翻译代谢成像生物标志物对针对异柠檬酸脱氢酶 1 (IDH1) 的先进临床相关疗法的反应突变IDH1神经胶质瘤的治疗。 IDH1 突变是一种“驱动突变”，存在于 70-90% 的低危人群中。级胶质瘤和继发性升级的胶质母细胞瘤。努力改善突变 IDH1 的治疗肿瘤，新的治疗方法已经开发出来，数据显示 siRNA 靶向野生型和（野生型）和突变型 IDH1，以及目前正在临床试验中的新双重（野生型/突变型）IDH 抑制剂，导致了一个明确的结果回复。然而，没有无创成像方法可用于评估药物靶标结合或预测反应。在本次资助的第一个资助期内，我们发现了几种突变 IDH1 驱动的 1H 磁共振波谱（MRS）可检测代谢改变，并开发出新型翻译基于超极化 13C MRS 的成像方法可告知突变的存在。我们的初步数据表明，对新兴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，但并非所有相关的超极化 13C MRS 可检测的代谢通量，可能反映了 wt IDH1 的抑制。此外，水平谷胱甘肽 (GSH) 以及 GSH 与其氧化形式 GSSG 的比率下降，表明可额外成像与反应相关的代谢反应。因此，我们假设使用我们之前的一些鉴定出突变 IDH1 的 MRS 生物标志物以及氧化还原状态的成像生物标志物，将有可能监测进入临床的双重 IDH 抑制剂的治疗效果。目标 1. 鉴定 1H 和超极化 13C MRS 可检测的代谢生物标志物突变 IDH1 细胞对新型 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 13C MRS 来识别可成像的代谢通过抑制细胞增殖来确定与治疗反应独特相关的改变和/或克隆形成潜力。目标 2. 从机制上验证 1H 和超极化 13C MRS 成像反应生物标志物。我们将使用一系列生化、细胞和分子生物学测定以及特定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. 体内确认 1H 和超极化 13C MRS 代谢成像生物标志物突变 IDH1 肿瘤对新型 IDH 靶向疗法的肿瘤反应指标。我们将治疗荷瘤小鼠，并使用具有 1H 和超极化 13C MRSI 的 MRI，纵向监测治疗肿瘤生长和代谢，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/或动物存活评估来预测反应。

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）

Late-stage deuteration of 13C-enriched substrates for T1 prolongation in hyperpolarized 13C MRI.

富含 13C 的底物的后期氘化可实现超极化 13C MRI 中的 T1 延长。

DOI：
发表时间：
2018-05-17
期刊：
影响因子：
0
作者：
Taglang, Céline;Korenchan, David E;von Morze, Cornelius;Yu, Justin;Najac, Chloé;Wang, Sinan;Blecha, Joseph E;Subramaniam, Sukumar;Bok, Robert;VanBrocklin, Henry F;Vigneron, Daniel B;Ronen, Sabrina M;Sriram, Renuka;Kurhanewicz, John;Wilson, D
通讯作者：
Wilson, D

In vivo investigation of hyperpolarized [1,3-13C2]acetoacetate as a metabolic probe in normal brain and in glioma.

超极化[1,3-13C2]乙酰乙酸作为正常脑和神经胶质瘤代谢探针的体内研究。

DOI：
发表时间：
2019
期刊：
影响因子：
4.6
作者：
Najac, Chloé;Radoul, Marina;Le Page, Lydia M;Batsios, Georgios;Subramani, Elavarasan;Viswanath, Pavithra;Gillespie, Anne Marie;Ronen, Sabrina M
通讯作者：
Ronen, Sabrina M

Molecular Imaging of Metabolic Reprograming in Mutant IDH Cells.

突变 IDH 细胞代谢重编程的分子成像。

DOI：
发表时间：
2016
期刊：
影响因子：
0
作者：
Viswanath, Pavithra;Chaumeil, Myriam M;Ronen, Sabrina M
通讯作者：
Ronen, Sabrina M

Mutant IDH1 expression is associated with down-regulation of monocarboxylate transporters.

突变的 IDH1 表达与单羧酸转运蛋白的下调相关。

DOI：
发表时间：
2016-06-07
期刊：
影响因子：
0
作者：
Viswanath, Pavithra;Najac, Chloe;Izquierdo;Pankov, Aleksandr;Hong, Chibo;Eriksson, Pia;Costello, Joseph F;Pieper, Russell O;Ronen, Sabrina M
通讯作者：
Ronen, Sabrina M

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：
发表时间：
2016-08-10
期刊：
影响因子：
4.6
作者：
Najac, Chloé;Chaumeil, Myriam M;Kohanbash, Gary;Guglielmetti, Caroline;Gordon, Jeremy W;Okada, Hideho;Ronen, Sabrina M
通讯作者：
Ronen, Sabrina M