Clinical development of cancer-specific MRS biomarkers in malignant gliomas

恶性胶质瘤癌症特异性 MRS 生物标志物的临床开发

基本信息

批准号：
9336267
负责人：
Changho Choi
金额：
$ 32.99万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-09-01 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9336267
关键词：
Active Sites Adult Adult Glioma Autoimmune Process Biological Biological Markers Blood Vessels Brain Brain Diseases Brain Mass Brain Neoplasms Brain imaging Cell Death Cell Proliferation Cells Citrates Clinical Clinical Trials Cortical Malformation Data Detection Development Diagnosis Differential Diagnosis Disease Early Diagnosis Encephalitis Enrollment Enzymes Evaluation Gadolinium Generations Genotype Glioblastoma Glioma Glycine Goals Image Incidence Infarction Infection Isocitrate Dehydrogenase Lesion Location Longitudinal Studies Magnetic Resonance Imaging Magnetic Resonance Spectroscopy Malignant - descriptor Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Measurable Measures Metabolic Metabolism Monitor Mutate Mutation Neurologist Normal tissue morphology Oncologist Outcome Patient Care Patients Phase Play Positioning Attribute Predictive Value Primary Brain Neoplasms Research Resolution Scanning Scientist Slice Specificity System Therapeutic Time Tissues Triage Tumor Markers Tumor stage Vasculitis Venous Work anticancer research cancer biomarkers cancer cell cell growth clinical application clinical development clinical practice cohort imaging modality imaging study in vivo in vivo magnetic resonance spectroscopy inhibitor/antagonist insight lipid biosynthesis multidisciplinary mutant neoplastic cell nervous system disorder non-invasive imaging non-invasive monitor novel outcome forecast predictive of treatment response public health relevance radiologist spectroscopic imaging success tool treatment effect treatment response tumor tumor growth tumor heterogeneity tumor progression

项目摘要

DESCRIPTION (provided by applicant): Malignant gliomas represent the majority of primary brain tumors in adults and are among the most intractable tumors. Cancers reprogram their metabolism to meet the needs of rapid cell growth. Alterations in metabolite abundance may serve as biomarkers of malignancy, and the capability to monitor the changes non-invasively would have significant clinical utility in cancer. Gliomas often contain a specific metabolic activty that is predictive of the genotype and has predictive value with respect to tumor stage and patient survival. A high fraction of gliomas contain mutations in the metabolic enzymes, isocitrate dehydrogenase (IDH) 1 and 2. These heterozygous mutations are confined to the active site of the enzyme and result in a neomorphic activity that causes the mutant enzyme to produce an "oncometabolite", 2-hydroxyglutarate (2HG). Non-invasive identification of this onco-metabolite by MRS is therefore a major breakthrough in cancer research. Beyond simple detection of 2HG, our preliminary data show that 2HG is a remarkably sensitive biomarker for monitoring tumor progression and response to treatment in IDH mutated gliomas. Glycine (Gly) is a biomarker of tumor malignancy, as indicated in prior studies. Our data also indicate that citrate (Cit) is elevated in gliomas. Over the course of this preliminary study, there has been crucial need for 3D evaluation of these onco-metabolites within the tumor mass. Here, we propose to examine the clinical utility of 2HG, Gly and Cit, in a large cohort of subjects using multi-slice 2D MRSI at 3T. In order to accomplish this goal, we have assembled a multi-disciplinary work team of MR scientist, neuro-oncologist, neurologist, radiologist and biostatistician, who will contribute their expertise in the fields. The specific aims include, firs, an in-vivo MRS study for the disease specificity of 2HG (Aim 1). We will examine clinically proven non-glioma lesions who mimic glioma in clinical MRI. To increase the clinical applicability of the result, we will select non-enhancing brain diseases, given that IDH mutation occurs largely in grade-2 and -3 gliomas, which are often non-enhancing. Second, we will examine the clinical utility of 2HG, Gly, Cit and other metabolites in patients with IDH mutated gliomas (Aim 2). Third, we will examine the clinical utility of Gly, Cit and other metabolites in patients with IDH wild type gliomas (Aim 3). In Aim 2 and 3, the patients will undergo MRSI scans at multiple time points, and we will monitor the metabolic changes with tumor progression and in response to treatment. We anticipate our study will provide significant value in many aspects of management of gliomas. 3D evaluation of the cancer biomarkers using MRSI will provide biological insights for making the diagnosis of gliomas, tracking of infiltrative cells during follw up, and determining response to treatment. Success of the 2HG specificity study in non-glioma neurological diseases will provide an experimental evidence for use of non-invasive 2HG imaging as a triaging tool in the workup of a new brain mass.

描述（由申请人提供）：恶性神经胶质瘤代表了成人原发性脑肿瘤的大部分，并且是最难治疗的肿瘤之一。癌症重新编程其新陈代谢以满足细胞快速生长的需要。代谢物丰度的改变可以作为恶性肿瘤的生物标志物，并且非侵入性监测变化的能力将在癌症中具有重要的临床实用性。神经胶质瘤通常含有可预测基因型的特定代谢活性，并且对肿瘤分期和患者生存具有预测价值。大部分神经胶质瘤含有代谢酶异柠檬酸脱氢酶 (IDH) 1 和 2 的突变。这些杂合突变仅限于酶的活性位点，并导致新形态的活性，导致突变酶产生“致癌代谢物” , 2-羟基戊二酸 (2HG)。因此，通过 MRS 对这种肿瘤代谢物进行非侵入性鉴定是癌症研究的重大突破。除了简单检测 2HG 之外，我们的初步数据表明，2HG 是一种非常敏感的生物标志物，可用于监测 IDH 突变神经胶质瘤的肿瘤进展和治疗反应。如先前的研究所示，甘氨酸 (Gly) 是肿瘤恶性肿瘤的生物标志物。我们的数据还表明，神经胶质瘤中柠檬酸盐 (Cit) 升高。在这项初步研究的过程中，迫切需要对肿瘤块内的这些肿瘤代谢物进行 3D 评估。在这里，我们建议在一大群受试者中使用 3T 多切片 2D MRSI 来检查 2HG、Gly 和 Cit 的临床效用。为了实现这一目标，我们组建了一个由 MR 科学家、神经肿瘤学家、神经科医生、放射科医生和生物统计学家组成的多学科工作团队，他们将贡献自己在该领域的专业知识。具体目标首先包括针对 2HG 疾病特异性的体内 MRS 研究（目标 1）。我们将检查临床证实的在临床 MRI 中模仿神经胶质瘤的非神经胶质瘤病变。为了增加结果的临床适用性，我们将选择非增强脑部疾病，因为 IDH 突变主要发生在 2 级和 -3 级胶质瘤中，而这些胶质瘤通常是非增强的。其次，我们将研究 2HG、Gly、Cit 和其他代谢物在 IDH 突变神经胶质瘤患者中的临床效用（目标 2）。第三，我们将检查 Gly、Cit 和其他代谢物在 IDH 野生型胶质瘤患者中的临床效用（目标 3）。在目标 2 和 3 中，患者将在多个时间点接受 MRSI 扫描，我们将监测随着肿瘤进展和治疗反应的代谢变化。我们预计我们的研究将为神经胶质瘤治疗的许多方面提供重要价值。使用 MRSI 对癌症生物标志物进行 3D 评估将为神经胶质瘤的诊断、随访过程中浸润细胞的追踪以及确定治疗反应提供生物学见解。 2HG 特异性研究在非神经胶质瘤神经系统疾病中的成功将为使用非侵入性 2HG 成像作为新脑质量检查的分类工具提供实验证据。