Visualization of Diagnostic and Therapeutic Targets in Glioma With Molecular Imaging.

Andrei Iagaru,Chirag B. Patel,Deling Li,Liwei Zhang,Guofan Xu,Zhen Cheng,Zhaohui Zhu

doi:10.3389/fimmu.2020.592389

Abstract

Gliomas, particularly high-grade gliomas including glioblastoma (GBM), represent the most common and malignant types of primary brain cancer in adults, and carry a poor prognosis. GBM has been classified into distinct subgroups over the years based on cellular morphology, clinical characteristics, biomarkers, and neuroimaging findings. Based on these classifications, differences in therapeutic response and patient outcomes have been established. Recently, the identification of complex molecular signatures of GBM has led to the development of diverse targeted therapeutic regimens and translation into multiple clinical trials. Chemical-, peptide-, antibody-, and nanoparticle-based probes have been designed to target specific molecules in gliomas and then be visualized with multimodality molecular imaging (MI) techniques including positron emission tomography (PET), single-photon emission computed tomography (SPECT), near-infrared fluorescence (NIRF), bioluminescence imaging (BLI), and magnetic resonance imaging (MRI). Thus, multiple molecules of interest can now be noninvasively imaged to guide targeted therapies with a potential survival benefit. Here, we review developments in molecular-targeted diagnosis and therapy in glioma, MI of these targets, and MI monitoring of treatment response, with a focus on the biological mechanisms of these advanced molecular probes. MI probes have the potential to noninvasively demonstrate the pathophysiologic features of glioma for diagnostic, treatment, and response assessment considerations for various targeted therapies, including immunotherapy. However, most MI tracers are in preclinical development, with only integrin αVβ3 and isocitrate dehydrogenase (IDH)-mutant MI tracers having been translated to patients. Expanded international collaborations would accelerate translational research in the field of glioma MI.

Highlights

Gliomas, especially glioblastoma (GBM), are the most malignant primary brain tumors in adults [1]
The widely used oncologic and neurologic radiotracer, 18FFDG, has been employed for evaluating the efficacy of bevacizumab [the only U.S Food and Drug Administration (FDA)–approved targeted inhibitor for recurrent GBM [20]] for newly diagnosed and recurrent GBM [9, 10], and for monitoring efficacy of novel inhibitors against molecular targets of interest in glioma, such as c-Met [a receptor tyrosine kinase (RTK) whose ligand is hepatocyte growth factor] [16], phosphoinositide 3 (PI3)-kinase [21], mammalian target of rapamycin [22], and other RTKs [17]. These studies demonstrate that 18F-FDG positron emission tomography (PET)/computed tomography (PET/ CT) can potentially detect early metabolic changes that occur before alterations discernable on traditional anatomic magnetic resonance imaging (MRI) and can help predict overall survival (OS) in these patients
Several promising molecular targets have been identified, including mutant isocitrate dehydrogenase (IDH), platelet-derived growth factor receptor (PDGFR), vascular endothelial growth factor receptor (VEGFR), integrin avb3 receptor, epidermal growth factor receptor (EGFR), c-Met, etc., These molecules and their specific inhibitors have been studied in multiple trials, and we summarize the molecular imaging (MI) modalities that are being used to visualize them in the context of glioma therapy

Summary

INTRODUCTION

Especially glioblastoma (GBM), are the most malignant primary brain tumors in adults [1]. The widely used oncologic and neurologic radiotracer, 18FFDG, has been employed for evaluating the efficacy of bevacizumab [the only U.S Food and Drug Administration (FDA)–approved targeted inhibitor for recurrent GBM [20]] for newly diagnosed and recurrent GBM [9, 10], and for monitoring efficacy of novel inhibitors against molecular targets of interest in glioma, such as c-Met [a receptor tyrosine kinase (RTK) whose ligand is hepatocyte growth factor] [16], phosphoinositide 3 (PI3)-kinase [21], mammalian target of rapamycin (mTOR) [22], and other RTKs [17] These studies demonstrate that 18F-FDG PET/computed tomography (PET/ CT) can potentially detect early metabolic changes that occur before alterations discernable on traditional anatomic MRI (e.g., tumor volume) and can help predict OS in these patients. U87MG (subcutaneous in mice) 23 Glioma patients 7 Children with diffuse intrinsic pontine glioma

12 Newly diagnosed glioma patients

Findings

CONCLUSIONS AND PERSPECTIVES