Emerging insights into barriers to effective brain tumor therapeutics

Abstract

There is great promise that ongoing advances in the delivery of therapeutics to the central nervous system (CNS) combined with rapidly expanding knowledge of brain tumor patho-biology will provide new, more effective therapies. Brain tumors that form from brain cells, as opposed to those that come from other parts of the body, rarely metastasize outside of the CNS. Instead, the tumor cells invade deep into the brain itself, causing disruption in brain circuits, blood vessel and blood flow changes, and tissue swelling. Patients with the most common and deadly form, glioblastoma (GBM) rarely live more than 2 years even with the most aggressive treatments and often with devastating neurological consequences. Current treatments include maximal safe surgical removal or biopsy followed by radiation and chemotherapy to address the residual tumor mass and invading tumor cells. However, delivering effective and sustained treatments to these invading cells without damaging healthy brain tissue is a major challenge and focus of the emerging fields of nanomedicine and viral and cell-based therapies. New treatment strategies, particularly those directed against the invasive component of this devastating CNS disease, are sorely needed. In this review, we (1) discuss the history and evolution of treatments for GBM, (2) define and explore three critical barriers to improving therapeutic delivery to invasive brain tumors, specifically, the neuro-vascular unit as it relates to the blood brain barrier, the extra-cellular space in regard to the brain penetration barrier, and the tumor genetic heterogeneity and instability in association with the treatment efficacy barrier, and (3) identify promising new therapeutic delivery approaches that have the potential to address these barriers and create sustained, meaningful efficacy against GBM.

Keywords: advanced therapeutics; blood brain barrier; brain cancer; drug delivery; glioblastoma; immunotherapy; nanomedicine; nanotechnology.

Figure 1

Emerging insights into barriers to effective brain therapeutics. Drug therapies used or designed for the treatment of invading glioma cells are hindered by three significant CNS and tumor-related physio-anatomic barriers: (1) the neuro-vascular unit (NVU) [related to the blood brain barrier (BBB)], which regulates the trafficking of substances between the blood stream and the brain, (2) the extra-cellular space (ECS) [related to the brain tissue/tumor penetration barrier], which comprises 15–20% of the total brain volume and affects the flow of nutrients, metabolites, cytokines, neurotransmitters, and numerous other molecules within tumors and brain tissue (the ECS components are not depicted to simplify the image), and (3) genetic heterogeneity and instability [related to the treatment effectiveness barrier], which enables the development of treatment resistant cells and redundant pathogenic mechanisms including immunologic escape, angiogenesis, hyperproliferation, invasion, and drug resistance. *Copyright Ian Suk 2014 – Johns Hopkins University.

Figure 2

Improvements in median survival over time for patients undergoing various treatments for malignant glioma. Since the 1960s when corticosteroids were introduced for tumor-associated brain edema, there has been more than a quadrupling of the median survival for these patients (). More recently, combination chemotherapy regimens have been suggested to increase this median survival upwards of 20 months.

Figure 3

New approaches to brain tumor therapies. Some possibilities for this include enhancing drug permeability across the blood brain barrier/neurovascular unit, including temporary disruption of this interface using chemical (mannitol) and physical (ultrasound) means. The distribution of therapies may be enhanced using catheter-based convection enhanced approaches. Biodegradable polymer wafer, particle, and microchip reservoir systems are being explored further for timed and/or sustained release of drugs, as well as targeting tumor-specific structures. *Copyright Ian Suk 2012 – Johns Hopkins University.