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.

Anticancer drug candidate CBL0137, which inhibits histone chaperone FACT, is efficacious in preclinical orthotopic models of temozolomide-responsive and -resistant glioblastoma

“…Failure to penetrate the blood-brain barrier dooms many potential therapies of the CNS, 21 and the successful accumulation of CBL0137 in the brain, particularly the orthotopic GBM tumors, bodes well for the potential of this drug to treat CNS tumors. The accumulation of CBL0137 at higher levels in orthotopic GBM tumors than in normal brain is likely due to the greater abundance of DNA per gram of tissue in the hypercellular tumor compared with normal brain, to which CBL0137 binds.…”

“…The accumulation of CBL0137 at higher levels in orthotopic GBM tumors than in normal brain is likely due to the greater abundance of DNA per gram of tissue in the hypercellular tumor compared with normal brain, to which CBL0137 binds. Clinically, the blood-brain barrier is heterogeneously leaky in gliomas, 21 which would serve to enhance the ability of CBL0137 to cross this barrier and inhibit FACT.…”

Intramedullary spinal cord tumors: a review of current and future treatment strategies

“…Areas of new research have largely focused on 4 methods for enhancing local drug delivery: 1) enhancing drug permeability through the blood-brain barrier; 2) temporary disruption of the blood-brain barrier (e.g., ultrasound); 3) interstitial delivery of drugs (e.g., CED); and 4) the use of implantable polymer wafers. 68 Several methods for enhancing drug permeability have been investigated. These include modifying drugs with molecules known to initiate receptor-mediated transcytosis via the transferrin receptor 65 and lipoprotein receptor-related protein-1.…”

How Treatment Monitoring Is Influencing Treatment Decisions in Glioblastomas

“…More recently, genomic and molecular prognostic markers have emerged, including mutations in the isocitrate dehydrogenase1/2 (IDH1/2) genes and methylation of O 6 -methylguanine-DNA methyltransferase (MGMT) [4]. Restricted to the CNS, with extremely rare cases of metastasis, GBM is highly locally invasive with tumor cells found far from the main tumor mass, invariably leading to tumor recurrence [10].…”