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: 8968824
• 负责人: Ovidiu C Andronesi
• 金额: $ 20.04万
• 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 2017-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968824
• 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; Health; 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; 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 biomarker; imaging modality; improved; improved outcome; in vivo; innovation; interest; meetings; molecular imaging; motion sensitivity; mutant; nervous system disorder; novel therapeutics; patient subsets; prognostic; spectroscopic imaging; targeted agent; treatment response; tumor; tumor heterogeneity; 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)：迫切需要改善进展有限的原发恶性脑瘤患者的预后。目前，胶质瘤患者的5年生存率在人类恶性肿瘤中徘徊在34%左右。一幅更可怕的图景是胶质母细胞瘤，它的五年存活率不到5%，不幸的是，它代表了大多数成年人的原发恶性脑瘤。最近，发现异柠檬酸脱氢酶1和2(IDH1，2)突变在高达80%的不同类型的胶质瘤中被发现，同时有数据表明IDH突变是肿瘤发生的早期驱动因素，这为开发这种疾病的新治疗方法提供了一个令人兴奋的机会。许多研究小组和制药公司正处于非常高级的阶段，以获得针对突变IDH的药物，可以在人体临床试验中进行测试。在这种情况下，更好的成像工具对于加速新药从试验台到床边的转移至关重要。长期目标是建立新的体内分子成像方法，用于癌症的翻译研究，以促进对新疗法的理解和开发。活体肿瘤成像因其能够捕捉整个肿瘤的异质性和非侵袭性而备受关注。特别是，这项应用的目标是纵向成像和非侵入性量化2-羟基戊二酸(2HG)水平，在治疗过程中突变的IDH1胶质瘤患者。这些患者的一个关键的代谢改变是由于突变的IDH酶功能的获得而导致肿瘤性代谢物2HG的大量积累。在胶质瘤和其他几种IDH突变频繁的癌症中，高水平的2HG对IDH突变的特异性接近100%。因此，处理引起的突变IDH酶活性的变化应通过2HG水平的变化来反映。基于以上考虑，中心假设是2HG可以作为预后和药效学成像生物标记物，无创地量化和预测IDH1突变的胶质瘤患者的治疗反应。在申请者提供的强大初步数据的指导下，这一假设将通过追求以下两个具体目标来检验：1)开发和验证稳健的磁共振光谱成像(MRSI)方法，用于量化突变的IDH1胶质瘤患者的2HG；以及2)纵向成像和量化正在进行针对突变IDH1的临床试验的突变的IDH1胶质瘤患者的2HG水平。这项拟议研究的一个强有力的理由是，为了评估候选化合物是否有效地针对胶质瘤患者的突变IDH，除了MRSI，没有其他可行的替代方案。在第一个目标下，申请人已经证明可以明确检测2HG的MRSI方法将进一步改进，以具有更好的灵敏度和更低的变异性。为了实现这些目标，同一研究人员展示的几种技术，包括绝热激励、运动伪影和硬件漂移的快速捕获和实时校正，将与外部电子校准相结合，以进行绝对量化。在第二个目标下，将通过使用这些新开发的方法来确定患者对针对突变IDH1胶质瘤的药物的治疗反应。这种方法是创新的，因为它超越了目前诊断IDH1突变的重点，而是更实际的目的，即量化携带这种突变的患者的治疗反应。这项拟议的研究具有重要意义，因为它将确定突变的IDH1胶质瘤患者的药物作用，并促进对代谢紊乱在肿瘤启动和维持中所起作用的理解。这一知识对指导这一亚型胶质瘤的新治疗方法的开发非常重要，并有可能适用于IDH1突变频繁的其他癌症，以及各种代谢、神经和精神疾病。