Molecular MR-PET to characterize malignant transformation and identify therapeutic vulnerabilities in human IDH-mutant gliomas

分子 MR-PET 表征人类 IDH 突变神经胶质瘤的恶性转化并确定治疗脆弱性

• 批准号: 10750893
• 负责人: Nicholas S. Cho
• 金额: $ 4.01万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-01 至 2026-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10750893
• 关键词: Accounting; Acidity; Address; Affect; Anatomy; Area; Biological; Biological Markers; Biopsy; Blood - brain barrier anatomy; Blood Vessels; Blood Volume; Cell Density; Cell Proliferation; Cellularity; Characteristics; Classification; Clinical; Clinical Management; Codon Nucleotides; Diffusion; Diffusion Magnetic Resonance Imaging; Disease; Early identification; Enzymes; Event; Extravasation; Functional Imaging; Glioma; Glycolysis; Goals; Histologic; Histology; Human; Hypoxia; Hypoxia Inducible Factor; Image; Indolent; Intervention; Isocitrate Dehydrogenase; Magnetic Resonance Imaging; Malignant - descriptor; Malignant Glioma; Measurable; Measurement; Metabolic; Microvascular Proliferation; Modality; Molecular; Mutation; Nature; Operative Surgical Procedures; PECAM1 gene; Patients; Perfusion; Physiological; Positron-Emission Tomography; Process; Prognosis; Recurrence; S-Phase Fraction; Signal Transduction; Therapeutic; Therapeutic Intervention; Tissues; Treatment Failure; World Health Organization; anatomic imaging; angiogenesis; cerebral blood volume; contrast enhanced; density; fluorodeoxyglucose; follow-up; gain of function; image guided; imaging biomarker; improved; inhibitor; inhibitor therapy; insight; lactate dehydrogenase A; longitudinal analysis; magnetic resonance imaging biomarker; malignant phenotype; metabolic imaging; mutant; mutational status; neoplastic cell; new therapeutic target; non-invasive imaging; patient population; response; serial imaging; standard of care; targeted treatment; theories; treatment response; tumor; tumor growth; tumor microenvironment; uptake

PROJECT SUMMARY/ABSTRACT The World Health Organization (WHO) classification of gliomas has been steadily shifting from a histological classification towards a molecular classification. For example, isocitrate dehydrogenase (IDH) mutational status is a critical feature of the recent 2021 WHO classification. Compared to IDH-wild-type (IDH-wt) gliomas, IDH- mutant (IDH-m) gliomas have distinct clinical characteristics such as accounting for most low-grade gliomas (LGGs; grade 2), having better prognosis, growing slower, and affecting a younger patient population compared to IDH-wt gliomas. However, all WHO grade 2 IDHm gliomas are expected to eventually become malignant higher-grade (WHO grades 3-4) gliomas in a process known as malignant transformation. Upon malignant transformation, patients with IDHm gliomas have a significantly worse prognosis. Thus, early, non-invasive imaging biomarkers of IDHm glioma malignant transformation may allow for earlier identification of treatment failure and appropriate therapeutic interventions. Magnetic resonance imaging (MRI) is critical for the management of patients with IDHm gliomas. Currently, identification of malignant transformation in patients with IDHm gliomas involves the emergence of contrast- enhancing areas on T1-post-contrast MRI in previously non-enhancing grade 2 gliomas. However, advanced MRI biomarkers sensitive to acidity, perfusion, and cellular density may provide earlier identification of the tumor microenvironment changes associated with malignant transformation and earlier identification of treatment failure. Furthermore, combining our lab’s pH-sensitive MRI with metabolic positron emission tomography (PET) imaging may yield deeper insights into the tumor microenvironment, particularly for metabolic shifts associated with malignant transformation and new IDH inhibitor targeted therapies that inhibit the mutant IDH enzyme. As a result, this proposal seeks to identify molecular MR-PET biomarkers associated with malignant transformation and successful IDH inhibition of IDHm gliomas. In Specific Aim 1, we will establish a sequential order of advanced MRI biomarkers in IDHm gliomas undergoing malignant transformation using pH-sensitive, perfusion, diffusion, and anatomical MRI and then validate MR-PET biomarkers of IDHm gliomas with histopathological markers from targeted surgical biopsies. In Specific Aim 2, we will utilize pH-sensitive MRI and PET to evaluate metabolic perturbations in IDHm gliomas following successful IDH inhibitor therapy. The proposed studies may improve IDHm glioma management by establishing imaging biomarkers of malignant transformation and successful IDH inhibitor treatment response.

项目总结/摘要 世界卫生组织（WHO）对神经胶质瘤的分类一直在稳步地从组织学分类转向组织学分类。 分类向分子分类发展。例如，异柠檬酸脱氢酶（IDH）突变状态 是最近2021年世卫组织分类的一个关键特征。与IDH-野生型（IDH-wt）胶质瘤相比，IDH-野生型胶质瘤具有更高的细胞增殖活性。 突变型（IDH-m）胶质瘤具有独特的临床特征，例如占大多数低级别胶质瘤 (LGGs; 2级），具有更好的预后，生长较慢，并影响年轻的患者群体相比， IDH-wt胶质瘤。然而，预期所有WHO 2级IDHm胶质瘤最终都变成恶性的。 更高级别（WHO 3-4级）的胶质瘤在一个过程中被称为恶性转化。在恶性 在转化中，IDHm胶质瘤患者的预后显著更差。因此，早期，非侵入性 IDHm胶质瘤恶性转化的成像生物标志物可能允许早期识别治疗 失败和适当的治疗干预。 磁共振成像（MRI）对于IDHm胶质瘤患者的治疗至关重要。目前， IDHm胶质瘤患者恶性转化的鉴定涉及造影剂的出现， T1增强后MRI上先前无增强的2级胶质瘤的增强区域。然而，先进的 对酸度、灌注和细胞密度敏感的MRI生物标志物可以提供肿瘤的早期识别 与恶性转化相关的微环境变化和早期识别治疗 失败此外，结合我们实验室的pH敏感MRI和代谢正电子发射断层扫描（PET）， 成像可以更深入地了解肿瘤微环境，特别是与肿瘤微环境相关的代谢变化。 恶性转化和抑制突变IDH酶的新IDH抑制剂靶向疗法。作为 因此，该提案旨在确定与恶性转化相关的分子MR-PET生物标志物 以及IDHm胶质瘤的成功IDH抑制。 在特定目标1中，我们将建立IDHm胶质瘤中晚期MRI生物标志物的顺序 使用pH敏感、灌注、扩散和解剖MRI进行恶性转化，然后 用来自靶向手术活检的组织病理学标志物验证IDHm胶质瘤的MR-PET生物标志物。在 具体目标2，我们将利用pH敏感的MRI和PET来评估IDHm胶质瘤的代谢紊乱 在成功的IDH抑制剂治疗后。拟议的研究可能会通过以下方式改善IDHm胶质瘤的管理： 建立恶性转化和成功的IDH抑制剂治疗反应的成像生物标志物。