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

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.