Quantify treatment response in IDH1 mutant glioma patients with metabolic MRI

通过代谢 MRI 量化 IDH1 突变神经胶质瘤患者的治疗反应

• 批准号: 8568002
• 负责人: Ovidiu C Andronesi
• 金额: $ 20.06万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-08 至 2016-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8568002
• 关键词: Adult; American College of Radiology Imaging Network; Biochemical Pathway; Biological Markers; Biopsy; Calibration; Cancer Patient; Caring; Categories; Clinical Trials; Critiques; Data; Development; Diagnosis; Diagnosis Clinical Trials; Disease; Drug Targeting; Drug effect disorder; Electronics; Enzymes; Event; Genomics; Glioblastoma; Glioma; Glutamates; Goals; Heterogeneity; Human; Image; Imaging Device; Incidence; Individual; Innovative Therapy; Intervention; Isocitrate Dehydrogenase; Isocitrates; Knowledge; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Maintenance; Malignant Neoplasms; Malignant neoplasm of brain; Measurement; Measures; Mental disorders; Metabolic; Metabolic Diseases; Metabolic Pathway; Methodology; Methods; Mission; Morphologic artifacts; Motion; Mutation; Neurotransmitters; Oncogenic; Outcome; Patients; Pharmaceutical Preparations; Pharmacodynamics; Pharmacologic Substance; Phase; Proliferating; Public Health; Reproducibility; Research; Research Personnel; Role; Scanning; Scheme; Specificity; Survival Rate; Techniques; Testing; Therapeutic Agents; Time; Translational Research; Translations; Work; Writing; base; bench to bedside; cancer cell; cancer imaging; cancer therapy; clinical efficacy; cohort; gain of function; gamma-Aminobutyric Acid; imaging modality; improved; in vivo; innovation; interest; isocitrate; meetings; molecular imaging; motion sensitivity; mutant; nervous system disorder; novel therapeutics; prognostic; public health relevance; response; spectroscopic imaging; treatment response; tumor; tumor initiation; tumorigenesis

DESCRIPTION (provided by applicant): There is an urgent need to improve outcomes of patients with primary malignant brain tumors for which progress has been limited. At present, the 5-year survival rates for glioma patients hovers around 34% in the lower category among human malignancies. An even more gruesome picture is presented by glioblastoma that has less than 5% survival at five years, which unfortunately represents the majority of primary malignant brain tumors in adults. Recently, the discovery that mutations of isocitrate dehidrogenase 1 and 2 (IDH1,2) are found in up to 80% of different glioma types, together with data suggesting that IDH mutations are early drivers of tumorigenesis present an exciting opportunity for the development of new treatments for this disease. Many research groups and pharmaceutical companies are in very advanced phases for obtaining agents targeting mutant IDH that can be tested in human clinical trials. In this context, better imaging tools are criticalto accelerate the translation of new drugs from bench to bedside. The long-term goal is establishing new in vivo molecular imaging methods for translational research in cancer to facilitate the understanding and development of new therapies. In vivo cancer imaging is appealing especially because it can capture the entire tumor heterogeneity and it is non-invasive. In particular, the objective in this application is to image longitudinally and quantify non-invasively the levels of 2-hydroxyglutarate (2HG) in mutant IDH1 glioma patients during treatment. A key metabolic alteration in these patients is the large accumulation of the oncometabolite 2HG due to a gain of function of mutant IDH enzyme. High levels of 2HG was shown to approach 100% specificity for IDH mutations in gliomas and several other cancers with frequent IDH mutations. Hence, treatment induced changes in the activity of mutant IDH enzyme should be reflected by changes in 2HG levels. Based on the above considerations, the central hypothesis is that 2HG can be used as a prognostic and pharmacodynamic imaging biomarker to non-invasively quantify and predict treatment response in glioma patients with IDH1 mutations. Guided by strong preliminary data produced by the applicant, this hypothesis will be tested by pursuing the following two specific aims: 1) Develop and validate robust MR spectroscopic imaging (MRSI) methodology for quantifying 2HG in mutant IDH1 glioma patients; and 2) Longitudinal imaging and quantification of 2HG levels in mutant IDH1 glioma patients undergoing clinical trials targeting mutant IDH1. A strong rationale for the proposed research is that in order to assess whether candidate compounds are effectively targeting mutant IDH in glioma patients there are no other feasible alternatives than MRSI. Under the first aim, MRSI methods already proven by the applicant to unambiguously detect 2HG will be further improved to have better sensitivity and lower variability. To achieve these goals, several techniques shown by the same investigator, including adiabatic excitation, fast acquisition and real- time correction of motion artifacts and hardware drifts, will be combined with external electronic calibration for absolute quantification. Under the second aim, treatment response to drugs targeting mutant IDH1 gliomas will be determined in patients by employing these newly developed methods. The approach is innovative, because it goes beyond the current focus of diagnosing IDH1 mutations to the more practical purpose of quantifying treatment response in patients harboring this mutation. The proposed research is significant because it will determine drug action in mutant IDH1 glioma patients, and advance the understanding of the role that metabolic disturbances have in tumor initiation and maintenance. This knowledge is important to guide the development of new treatments for this subtype of gliomas, and has the potential to be applicable to other cancers where IDH1 mutations are frequent, as well as a variety of metabolic, neurological and psychiatric diseases.

描述（由申请人提供）：迫切需要改善原发性恶性脑肿瘤患者的预后，而进展受到限制。目前，胶质瘤患者的5年生存率在人类恶性肿瘤中徘徊在较低类别的34％中。胶质母细胞瘤表现出更加可怕的图片，五年的生存率不到5％，不幸的是，这代表了成年人中大多数原发性恶性脑肿瘤。最近，在多达80％的不同神经胶质瘤类型中发现了异位酸脱脂酶1和2（IDH1,2）突变的发现，以及数据表明IDH突变是肿瘤发生的早期驱动因素，这是一个令人兴奋的机会治疗这种疾病。许多研究小组和制药公司处于非常高级的阶段，用于获取可以在人类临床试验中测试突变体IDH的代理。在这种情况下，更好的成像工具至关重要，可以加速新药从长凳到床边的转换。长期目标是建立新的体内分子成像方法，用于癌症的转化研究，以促进新疗法的理解和发展。体内癌症成像具有吸引力，尤其是因为它可以捕获整个肿瘤异质性，并且它是无创的。特别是，本应用的目的是在治疗期间在突变体IDH1神经瘤患者中对2-羟基戊二酸（2HG）的2-羟基戊二酸（2HG）的水平进行非侵入性图像。这些患者的主要代谢改变是由于突变IDH酶功能的增加，oncometabolite 2Hg的大量积累。显示高水平的2HG在神经胶质瘤和其他具有频繁IDH突变的癌症中的IDH突变方面具有100％的特异性。因此，治疗诱导的突变体IDH酶活性的变化应由2Hg水平的变化反映。基于上述考虑，中心假设是2HG可以用作预后和药效学成像生物标志物，以非侵入性地量化和预测IDH1突变患者的治疗反应。在申请人产生的强有初步数据的指导下，该假设将通过追求以下两个具体目的来检验：1）开发和验证可量化强大的MR光谱成像（MRSI）方法，用于在突变体IDH1胶质瘤患者中量化2HG； 2）突变体IDH1神经胶质瘤患者的纵向成像和2HG水平的定量，该患者接受了靶向突变体IDH1的临床试验。拟议研究的强烈理由是，为了评估候选化合物在神经胶质瘤患者中是否有效靶向突变体IDH，除了MRSI以外，没有其他可行的选择。在第一个目标下，申请人已经证明了明确检测2HG的MRSI方法将进一步提高，以具有更好的敏感性和较低的可变性。为了实现这些目标，同一研究者显示的几种技术，包括绝热激发，快速获取和运动伪像和硬件漂移的实时校正，将与外部电子校准相结合，以实现绝对量化。在第二个目标下，将通过采用这些新开发的方法来确定对靶向突变IDH1胶质瘤的药物的治疗反应。该方法具有创新性，因为它超出了当前诊断IDH1突变的重点，即在具有该突变的患者中量化治疗反应的更实际目的。拟议的研究很重要，因为它将确定突变IDH1神经胶质瘤患者的药物作用，并提高对代谢障碍在肿瘤启动和维持中具有的作用的理解。这些知识对于指导这种神经胶质瘤亚型的新疗法的开发很重要，并且有可能适用于经常发生IDH1突变以及各种代谢，神经和精神病学疾病的其他癌症。