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

项目摘要/摘要 世界卫生组织(WHO)对胶质瘤的分类一直在稳步从组织学 从分子分类到分子分类。例如，异柠檬酸脱氢酶(IDH)突变状态 是世卫组织最近2021年分类的一个关键特征。与IDH-野生型(IDH-wt)胶质瘤相比，IDH-wt- 突变型(idh-m)胶质瘤具有明显的临床特征，如大多数低级别胶质瘤。 (LGGs；2级)，预后较好，生长较慢，影响较年轻的患者群体 到IDH-WT神经胶质瘤。然而，所有世卫组织2级IDHm胶质瘤预计最终都会变得恶性 较高级别(世界卫生组织3-4级)的胶质瘤在一个称为恶变的过程中。论恶性 在转化过程中，IDHm胶质瘤患者的预后明显较差。因此，早期、非侵入性 IDHm胶质瘤恶变的成像生物标志物可能有助于更早地识别治疗 失败和适当的治疗干预。 磁共振成像(MRI)对IDHm胶质瘤患者的治疗至关重要。目前， IDHm胶质瘤患者恶变的鉴别包括造影剂的出现。 先前无强化的2级胶质瘤在T1增强后MRI上的强化区域。但是，高级 对酸度、灌注和细胞密度敏感的mri生物标志物可提供肿瘤的早期识别。 与恶变相关的微环境变化和治疗的早期识别 失败了。此外，将我们实验室的pH敏感磁共振成像与代谢正电子发射断层扫描(PET)相结合 成像可以更深入地了解肿瘤的微环境，特别是与之相关的代谢变化。 随着恶性转化和新的IDH抑制剂靶向治疗，抑制突变的IDH酶。AS 因此，这项提案试图确定与恶性转化相关的分子MR-PET生物标记物 IDHm胶质瘤的IDH抑制成功。 在特定的目标1中，我们将建立IDHm胶质瘤的高级mri生物标记物的顺序。 使用pH敏感、灌注、扩散和解剖MRI进行恶变，然后 用靶向手术活检的组织病理学标记物验证IDHm胶质瘤的MR-PET生物标记物。在……里面 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IDH抑制剂治疗成功后。拟议的研究可能通过以下方式改善IDHm胶质瘤的治疗 建立恶性转化和IDH抑制剂治疗反应成功的影像生物标志物。

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.