Neuroimaging Studies Evaluating Effective Therapies for High-Grade Glioma

Abstract

High-grade glioma (HGG) is one of the most aggressive types of brain tumours, with a median survival limited to 15 months. The ability to develop new effective therapies for HGG patients has been hampered by the heterogeneous structural and physiological properties of the blood-brain barrier (BBB) in the tumour, which largely influence the efficiency of delivery targeting therapies to the entire population of tumour cells. This thesis focuses on using neuroimaging techniques to investigate how the structural and physiological properties of the BBB in HGG affect the targeted delivery of macromolecular drugs, such as antibodies and nanomedicines. Additionally, this work involves the development of neuroimaging analysis pipelines for evaluating novel strategies for more effective therapies for HGG.The first part of this thesis provides an overview of HGG, discussing the disease’s pathology, current standard of care, limitations in improving overall patient survival and the central role of the BBB in hindering efficient delivery of tumour-targeting drugs. A review of the current strategies for tumour vasculature remodelling to improve drug delivery to brain tumours is presented, together with the evaluation of the role of neuroimaging in the development of biomarkers of BBB disruption and permeability.The second part of the thesis demonstrates how the selection of preclinical animal models of HGG that are able to reproduce the heterogeneous BBB characteristics of HGG patients is key to the clinical translation of new therapies. Contrast enhanced (CE) and dynamic CE (DCE) MRI are used together with histology to show that a patient-derived xenograft model of HGG better reproduces the extent of BBB disruption and permeability of recurrent HGG patients than the currently most widely used cell-line xenograft model, and therefore, is a better preclinical platform for testing novel therapies for HGG. Considerations on the choice of kinetic modelling parameters for BBB permeability assessments and perspectives on the role of comparative oncology for HGG are also discussed.The third part of the thesis focuses on the use of the characterised patient-derived xenograft model of HGG to perform a preclinical trial evaluating the efficiency of MR-guided focused ultrasound (FUS) as a therapeutic strategy to modulate the BBB and enhance delivery of a large tumour-targeting antibody in non-enhancing infiltrating tumour lying behind an intact BBB. In this study, a combination of MRI and PET imaging techniques are used to demonstrate that FUS treatment causes a temporary opening of the BBB that allows for higher accumulation of antibodies into the infiltrating tumour regions. The report of positive preclinical outcomes is followed by a discussion on important considerations for the translation of FUS into clinical trials, with particular focus on the need for standards for the selection of contrast agents and sonication parameters, but also on the potential opportunities that FUS offers to the exploration of immunotherapies for HGG.Finally, the last part of the thesis focuses on the development and testing of a neuroimaging analysis pipeline for the evaluation of outcomes of clinical trials in Neuro-oncology and for the discovery of novel imaging biomarkers for recurrent HGG. This pipeline is tested on a small dataset from a pilot clinical trial investigating the theranostic potential of a PSMA-targeting peptide in patients with recurrent HGG. In particular, the analysis of MRI, PET and CT images is used to assess the ability of the PSMA-targeting peptide to selectively accumulate in the entire tumour mass, and to act as an imaging biomarker with several potential applications for the diagnosis, prognosis and secondary treatment planning of recurrent HGG patients.In summary, this thesis not only highlights the importance of overcoming the limitations posed by the BBB to promote the clinical translation of emerging macromolecular drugs for HGG, but it also unveils the power of neuroimaging as a longitudinal biomarker to evaluate therapeutic strategies and support clinical decision-making.