Magnetic resonance imaging-guided intracranial resection of glioblastoma tumors in patient-derived orthotopic xenografts leads to clinically relevant tumor recurrence

Abstract

Abstract Background Preclinical in vivo cancer models are essential tools for investigating tumor progression and response to treatment prior to clinical trials. Although treatment modalities are regularly assessed in mice upon tumor growth in vivo, surgical resection remains challenging, particularly in the orthotopic site. Here, we report a successful surgical resection of glioblastoma (GBM) in patient-derived orthotopic xenografts (PDOXs). Methods We derived a cohort of 46 GBM PDOX models accurately recapitulating human disease in mice. To assess feasibility of surgical resection in PDOXs, we selected two models representing histopathological features of GBM tumors, including diffuse growth into the mouse brain. Tumor growth was detected with magnetic resonance imaging (MRI). Surgical resection in the mouse brains was performed based on MRI-guided coordinates. Survival study followed by immunohistochemistry-based evaluation of recurrent tumors allowed for assessment of clinically relevant parameters. Results We show that a surgical resection protocol in mice carrying diffuse GBM tumors in the brain leads to clinically relevant outcomes. We demonstrate the utility of MRI for the noninvasive assessment of in vivo tumor growth, preoperative programming of resection coordinates and follow-up of tumor recurrence. Similar to neurosurgery in patients, we achieved a near total to complete extent of tumor resection, and mice with resected tumors presented significantly increased survival. The remaining unresected GBM cells that invaded the normal mouse brain prior to surgery regrew tumors with similar histopathological features and tumor microenvironments to the primary tumors. Conclusions Our data positions GBM PDOXs developed in mouse brains as a valuable preclinical model for conducting therapeutic studies that involve surgical tumor resection. Additionally, these models hold promise for the development of enhanced image-guided surgery protocols.