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

• 批准号: 9118131
• 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
• 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/9118131
• 关键词: Active Sites; Adult; Adult Glioma; Autoimmune Process; Biological; Biological Markers; Blood Vessels; Brain; Brain Diseases; Brain Mass; Brain Neoplasms; Cell Death; Cell Proliferation; Cells; Citrates; Clinical; Clinical Trials; Cortical Malformation; Data; Detection; Development; Diagnosis; Diagnostic Neoplasm Staging; Differential Diagnosis; Disease; Early Diagnosis; Encephalitis; Enrollment; Enzymes; Evaluation; Gadolinium; Generations; Genotype; Glioblastoma; Glioma; Glycine; Goals; Health; 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; Weight; Work; anticancer research; cancer biomarkers; cancer cell; cell growth; clinical application; clinical practice; cohort; gadolinium oxide; imaging modality; in vivo; inhibitor/antagonist; insight; lipid biosynthesis; meetings; mutant; neoplastic cell; nervous system disorder; non-invasive imaging; novel; outcome forecast; radiologist; success; tool; treatment effect; treatment response; tumor; tumor growth; tumor heterogeneity; tumor progression

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(申请人提供)：恶性胶质瘤是大多数成人原发脑肿瘤，也是最难治疗的肿瘤之一。癌症重新规划他们的新陈代谢，以满足细胞快速生长的需要。代谢产物丰度的改变可以作为恶性肿瘤的生物标志物，非侵入性监测这种变化的能力将在癌症中具有重要的临床应用价值。胶质瘤通常含有一种特定的代谢活性，它可以预测基因的类型，并对肿瘤的分期和患者的生存有预测价值。高比例的胶质瘤含有代谢酶异柠檬酸脱氢酶(IDH)1和2的突变。这些杂合性突变仅限于酶的活性部位，并导致新的活性，导致突变酶产生“肿瘤代谢物”--2-羟基戊二酸(2HG)。因此，利用MRS对这种肿瘤代谢物进行非侵入性鉴定是癌症研究的一项重大突破。除了2HG的简单检测外，我们的初步数据显示，2HG是一种非常敏感的生物标志物，用于监测IDH突变胶质瘤的肿瘤进展和治疗反应。甘氨酸(Gly)是肿瘤恶性程度的生物标志物，已有研究表明。我们的数据还表明，在胶质瘤中，柠檬酸盐(Cit)水平升高。在这项初步研究的过程中，迫切需要对肿瘤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的多层2D MRSI来检验2HG、Gly和Cit的临床应用。为了实现这一目标，我们组建了一个由科学家先生、神经肿瘤学家、神经病学家、放射学家和生物统计学家组成的多学科工作组，他们将在该领域提供专业知识。具体目标包括，第一，2HG疾病特异性的体内MRS研究(目标1)。我们将在临床MRI中检查临床证实的类似于胶质瘤的非胶质瘤病变。为了增加结果的临床适用性，我们将选择无强化的脑部疾病，因为IDH突变主要发生在2级和3级胶质瘤中，这两种肿瘤通常是无强化的。其次，我们将研究2HG、Gly、Cit和其他代谢物在IDH突变胶质瘤患者中的临床应用(目标2)。第三，我们将研究Gly、Cit和其他代谢物在IDH野生型胶质瘤患者中的临床应用(AIM 3)。在目标2和目标3中，患者将在多个时间点进行MRSI扫描，我们将监测随着肿瘤进展和治疗反应而发生的代谢变化。我们期待我们的研究将在胶质瘤治疗的许多方面提供重要的价值。使用MRSI对肿瘤生物标志物进行三维评估将为胶质瘤的诊断、追踪浸润性细胞和确定治疗反应提供生物学见解。在非神经胶质瘤神经系统疾病中2HG特异性研究的成功将为在新的脑肿块检查中使用非侵入性2HG成像作为分类工具提供实验证据。