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）：迫切需要改善进展有限的原发性恶性脑肿瘤患者的结局。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。一个更可怕的画面是胶质母细胞瘤，五年生存率不到5%，不幸的是，这代表了成年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（IDH 1，2）的突变在高达80%的不同胶质瘤类型中被发现，连同表明IDH突变是肿瘤发生的早期驱动因素的数据一起，为开发针对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非常先进的阶段，以获得可以在人体临床试验中测试的靶向突变IDH的药物。在这种情况下，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。特别地，本申请的目的是在治疗期间对突变IDH 1神经胶质瘤患者中的2-羟基戊二酸（2 HG）水平进行纵向成像和非侵入性定量。这些患者中的关键代谢改变是由于突变IDH酶的功能获得而导致癌代谢物2 HG的大量积累。高水平的2 HG显示出对神经胶质瘤和具有频繁IDH突变的几种其他癌症中的IDH突变接近100%特异性。因此，治疗诱导的突变IDH酶活性变化应反映在2 HG水平的变化。基于上述考虑，中心假设是2 HG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具有IDH 1突变的胶质瘤患者的治疗反应。在申请人产生的强有力的初步数据的指导下，将通过追求以下两个具体目标来测试该假设：1）开发并验证用于定量突变IDHl神经胶质瘤患者中的2 HG的稳健的MR光谱成像（MRSI）方法;以及2）经历靶向突变IDHl的临床试验的突变IDHl神经胶质瘤患者中的2 HG水平的纵向成像和定量。提出的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靶向神经胶质瘤患者中的突变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2 HG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，由同一研究者所展示的几种技术，包括绝热激励、快速采集和运动伪影和硬件漂移的真实的时间校正，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，将通过采用这些新开发的方法来确定患者对靶向突变IDH 1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IDH 1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的目的。这项研究意义重大，因为它将确定药物在突变型IDH 1胶质瘤患者中的作用，并促进对代谢紊乱在肿瘤发生和维持中作用的理解。这一知识对于指导这种胶质瘤亚型的新治疗方法的开发非常重要，并且有可能适用于IDH 1突变频繁的其他癌症，以及各种代谢，神经和精神疾病。