Blood-Brain Barrier in Brain Tumors: Biology and Clinical Relevance

Abstract

The presence of barriers, such as the blood-brain barrier (BBB) and brain-tumor barrier (BTB), limits the penetration of antineoplastic drugs into the brain, resulting in poor response to treatments. Many techniques have been developed to overcome the presence of these barriers, including direct injections of substances by intranasal or intrathecal routes, chemical modification of drugs or constituents of BBB, inhibition of efflux pumps, physical disruption of BBB by radiofrequency electromagnetic radiation (EMP), laser-induced thermal therapy (LITT), focused ultrasounds (FUS) combined with microbubbles and convection enhanced delivery (CED). However, most of these strategies have been tested only in preclinical models or in phase 1-2 trials, and none of them have been approved for treatment of brain tumors yet. Concerning the treatment of brain metastases, many molecules have been developed in the last years with a better penetration across BBB (new generation tyrosine kinase inhibitors like osimertinib for non-small-cell lung carcinoma and neratinib/tucatinib for breast cancer), resulting in better progression-free survival and overall survival compared to older molecules. Promising studies concerning neural stem cells, CAR-T (chimeric antigen receptors) strategies and immunotherapy with checkpoint inhibitors are ongoing.

Keywords: blood-brain barrier (BBB); brain–tumor barrier (BTB); chemotherapy; convection-enhanced delivery (CED); focused ultrasounds (FUS); nanoparticles (NP); neurovascular unit (NVU).

Figure 1

Overview of the neurovascular unit in brains harbouring tumors. The increased expression of molecules like metalloproteinases (MMP2-MMP9) and VEGF induces a breakdown of the BBB (especially the tight junctions of the endothelium) and enhances the penetration of the tumoral cells. Astrocytes contribute to the extravasation of the tumoral cells by expressing cytokines and growth factors. Modified from Pedrosa et al. [32].