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: 8698353
• 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 2015-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698353
• 关键词: Adult; American College of Radiology Imaging Network; Biochemical Pathway; Biological Markers; Biopsy; Calibration; Cancer Patient; Caring; Categories; Clinical Trials; Data; Development; Diagnosis; Diagnosis Clinical Trials; Disease; Drug Targeting; Drug effect disorder; Electronics; Enzymes; Event; Genomics; Glioblastoma; Glioma; Glutamates; Goals; Health; Heterogeneity; Human; Image; Imaging Device; Incidence; 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; base; bench to bedside; cancer cell; cancer imaging; cancer therapy; clinical efficacy; cohort; gain of function; gamma-Aminobutyric Acid; imaging biomarker; imaging modality; improved; in vivo; innovation; interest; isocitrate; molecular imaging; motion sensitivity; mutant; nervous system disorder; novel therapeutics; prognostic; 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，但进展有限。目前，胶质瘤患者的5年生存率徘徊在34%左右，在人类恶性肿瘤中属于较低类别。更可怕的是胶质母细胞瘤，其五年生存率不到 5%，不幸的是，它代表了成人原发性恶性脑肿瘤的大多数。最近，发现异柠檬酸脱氢酶 1 和 2 (IDH1,2) 突变存在于高达 80% 的不同神经胶质瘤类型中，并且数据表明 IDH 突变是肿瘤发生的早期驱动因素，这为开发该疾病的新疗法提供了令人兴奋的机会。许多研究小组和制药公司正处于获得可在人体临床试验中测试的针对突变 IDH 的药物方面的非常先进的阶段。在这种背景下，更好的成像工具对于加速新药从实验室到临床的转化至关重要。长期目标是为癌症转化研究建立新的体内分子成像方法，以促进新疗法的理解和开发。体内癌症成像特别有吸引力，因为它可以捕获整个肿瘤异质性并且是非侵入性的。特别是，本应用的目的是对突变 IDH1 神经胶质瘤患者在治疗期间的 2-羟基戊二酸 (2HG) 水平进行纵向成像和非侵入性定量。这些患者的一个关键代谢改变是由于突变 IDH 酶的功能获得而导致致癌代谢物 2HG 的大量积累。高水平的 2HG 对神经胶质瘤和其他几种经常出现 IDH 突变的癌症的 IDH 突变具有接近 100% 的特异性。因此，治疗引起的突变 IDH 酶活性变化应通过 2HG 水平的变化来反映。基于上述考虑，中心假设是2HG可以用作预后和药效成像生物标志物，以非侵入性量化和预测IDH1突变胶质瘤患者的治疗反应。在申请人提供的强有力的初步数据的指导下，该假设将通过追求以下两个具体目标进行检验：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IDH1神经胶质瘤患者的2HG； 2) 接受针对突变 IDH1 的临床试验的突变 IDH1 神经胶质瘤患者的 2HG 水平的纵向成像和定量。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能有效靶向神经胶质瘤患者的突变 IDH，除了 MRSI 之外，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，同一位研究者展示的几种技术，包括绝热激励、快速采集以及运动伪影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患者对针对突变 IDH1 神经胶质瘤的药物的治疗反应。该方法具有创新性，因为它超越了当前诊断 IDH1 突变的重点，达到了量化携带这种突变的患者的治疗反应的更实际目的。拟议的研究意义重大，因为它将确定突变 IDH1 神经胶质瘤患者的药物作用，并增进对代谢紊乱在肿瘤发生和维持中的作用的理解。这些知识对于指导这种神经胶质瘤亚型新疗法的开发非常重要，并且有可能适用于 IDH1 突变频繁的其他癌症以及各种代谢、神经和精神疾病。