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（由申请人提供）：恶性神经胶质瘤代表大多数成人原发性脑肿瘤，是最棘手的肿瘤之一。癌症重新编程了新陈代谢，以满足快速细胞生长的需求。代谢物丰度的改变可能是恶性肿瘤的生物标志物，并且非侵入性地监测变化的能力将在癌症中具有显着的临床效用。神经胶质瘤通常包含一种特定的代谢活性，该活性可预测基因型，并且在肿瘤期和患者生存方面具有预测价值。 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).因此，在癌症研究中，MRS对这种非代谢物的无创鉴定是一个重大突破。除了简单地检测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，用于监测IDH突变的神经胶质瘤中肿瘤进展和对治疗的反应。甘氨酸（Gly）是肿瘤恶性肿瘤的生物标志物，如先前的研究所示。我们的数据还表明，柠檬酸盐（CIT）在神经胶质瘤中升高。在这项初步研究的过程中，对肿瘤质量内这些onco-亚代谢产物的3D评估至关重要。在这里，我们建议在大量受试者中使用多板2D MRSI在3T时检查2Hg，Gly和CIT的临床实用性。为了实现这一目标，我们组建了一个多学科的工作团队，科学家，神经综合学家，神经科医生，放射科医生和生物统计学家将在该领域贡献他们的专业知识。具体目的包括FIRS，一项体内MRS MRS研究2HG的疾病特异性研究（AIM 1）。我们将检查模仿临床MRI的临床证明的非胶质瘤病变。为了提高结果的临床适用性，我们将选择非增强脑疾病，因为IDH突变主要发生在2级和-3级胶质瘤中，这通常是非增强的。其次，我们将检查IDH突变的神经胶质瘤患者中2Hg，Gly，CIT和其他代谢产物的临床实用性（AIM 2）。第三，我们将研究IDH野生型神经胶质瘤患者中GLY，CIT和其他代谢产物的临床实用性（AIM 3）。在AIM 2和3中，患者将在多个时间点进行MRSI扫描，我们将随着肿瘤进展和对治疗的反应来监测代谢变化。我们预计我们的研究将在神经胶质瘤管理的许多方面具有重要价值。使用MRSI对癌症生物标志物的3D评估将提供生物学见解，以诊断神经胶质瘤，在FOLLW中跟踪浸润细胞以及确定对治疗的反应。 2HG特异性研究在非葡萄膜瘤神经系统疾病中的成功将为使用非侵入性2HG成像作为新脑部肿块的分域工具提供实验证据。