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: 8897306
• 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/8897306
• 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; Heterogeneity; 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; Relative (related person); Research; Resolution; Scanning; Scientist; Slice; Specificity; System; Therapeutic; Time; Tissues; Triage; Tumor Markers; Tumor stage; Vasculitis; Venous; Weight; Work; anticancer research; 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; response; success; tool; treatment effect; treatment response; tumor; tumor growth; 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）：恶性神经胶质瘤占成人原发性脑肿瘤的大多数，是最难治的肿瘤之一。癌症会重新编程其新陈代谢以满足快速细胞生长的需要。代谢物丰度的改变可以作为恶性肿瘤的生物标志物，并且非侵入性地监测变化的能力将在癌症中具有显著的临床实用性。神经胶质瘤通常含有特定的代谢活性，其可预测基因型，并对肿瘤分期和患者生存具有预测价值。高比例的神经胶质瘤含有代谢酶异柠檬酸脱氢酶（IDH）1和2的突变。这些杂合突变局限于酶的活性位点，并产生新变体活性，导致突变酶产生“癌代谢物”2-羟基戊二酸（2 HG）。因此，通过MRS对这种致癌代谢物的非侵入性鉴定是癌症研究中的重大突破。除了简单检测2 HG之外，我们的初步数据表明2 HG是监测IDH突变胶质瘤的肿瘤进展和治疗反应的非常敏感的生物标志物。甘氨酸（Gly）是肿瘤恶性程度的生物标志物，如先前研究所示。我们的数据还表明，柠檬酸盐（Cit）在胶质瘤中升高。在这项初步研究的过程中，迫切需要对肿瘤块内的这些癌代谢物进行3D评估。在这里，我们建议检查2 HG，Gly和Cit的临床效用，在一个大型队列的受试者使用多层2D MRSI在3 T。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，神经学家，放射科医生和生物统计学家组成的多学科工作团队，他们将在该领域贡献自己的专业知识。具体目标包括，首先，针对2 HG的疾病特异性的体内MRS研究（目标1）。我们将检查临床证实的非胶质瘤病变谁模仿胶质瘤在临床MRI。为了增加结果的临床适用性，我们将选择非增强性脑疾病，因为IDH突变主要发生在2级和3级胶质瘤中，这些胶质瘤通常是非增强性的。其次，我们将检查2 HG、Gly、Cit和其他代谢物在IDH突变的神经胶质瘤患者中的临床效用（目的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（目的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。我们期望我们的研究将在神经胶质瘤的管理的许多方面提供重要的价值。使用MRSI对癌症生物标志物的3D评估将为神经胶质瘤的诊断、随访期间浸润细胞的跟踪以及确定对治疗的反应提供生物学见解。2 HG特异性研究在非胶质瘤神经系统疾病中的成功将为使用非侵入性2 HG成像作为新的脑肿块的后处理中的分类工具提供实验证据。