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.

项目摘要/摘要 神经胶质瘤的世界卫生组织（WHO）分类一直从组织学稳步转移 分子分类的分类。例如，异位酸盐脱氢酶（IDH）突变状态 是最近2021年WHO分类的关键特征。与IDH野生型（IDH-WT）Gliomas相比，IDH- 突变体（IDH-M）神经胶质瘤具有不同的临床特征，例如大多数低级神经胶质瘤 （LGGS; 2级），比较较慢，越来越慢，并且影响年轻的患者人群 到IDH-WT神经胶质瘤。但是，所有2年级IDHM Gliomas都预计最终会变得恶性 在称为恶性转化的过程中，高级（WHO 3-4年级）神经胶质瘤。恶性 转化，IDHM胶质瘤患者的预后明显较差。那是早期的，无创的 IDHM神经胶质瘤恶性转化的成像生物标志物可能允许早期鉴定治疗 失败和适当的治疗干预措施。 磁共振成像（MRI）对于管理IDHM胶质瘤患者的管理至关重要。现在， 鉴定IDHM神经胶质瘤患者的恶性转化涉及对比的出现 在以前非增强2级神经膜瘤中T1-POST对比度MRI的区域增强区域。但是，先进 MRI生物标志物对酸度，灌注和细胞密度敏感 微环境变化与恶性转化和治疗的早期鉴定有关 失败。此外，将我们实验室的pH敏感MRI与代谢正电子发射断层扫描（PET）相结合 成像可能会对肿瘤微环境产生更深入的见解，特别是对于相关的代谢转移 具有恶性转化和新的IDH抑制剂的靶向疗法，可抑制突变体IDH酶。作为 结果，该提案旨在鉴定与恶性转化相关的分子MR-PET生物标志物 并成功地抑制了IDHM胶质瘤。 在特定的目标1中，我们将在IDHM Gliomas中建立高级MRI生物标志物的顺序顺序 使用pH敏感，灌注，扩散和解剖学MRI进行恶性转化，然后 验证IDHM神经胶质瘤的MR-PET生物标志物，并具有来自靶向手术活检的组织病理学标记。在 具体目标2，我们将利用对pH敏感的MRI和PET评估IDHM胶质瘤中的代谢扰动 成功的IDH抑制剂治疗后。拟议的研究可以通过 建立恶性转化和成功IDH抑制剂治疗反应的成像生物标志物。