Developments in Blood-Brain Barrier Penetrance and Drug Repurposing for Improved Treatment of Glioblastoma

Abstract

Glioblastoma (GBM) is one of the most common, deadly, and difficult-to-treat adult brain tumors. Surgical removal of the tumor, followed by radiotherapy (RT) and temozolomide (TMZ) administration, is the current treatment modality, but this regimen only modestly improves overall patient survival. Invasion of cells into the surrounding healthy brain tissue prevents complete surgical resection and complicates treatment strategies with the goal of preserving neurological function. Despite significant efforts to increase our understanding of GBM, there have been relatively few therapeutic advances since 2005 and even fewer treatments designed to effectively treat recurrent tumors that are resistant to therapy. Thus, while there is a pressing need to move new treatments into the clinic, emerging evidence suggests that key features unique to GBM location and biology, the blood-brain barrier (BBB) and intratumoral molecular heterogeneity, respectively, stand as critical unresolved hurdles to effective therapy. Notably, genomic analyses of GBM tissues has led to the identification of numerous gene alterations that govern cell growth, invasion and survival signaling pathways; however, the drugs that show pre-clinical potential against signaling pathways mediated by these gene alterations cannot achieve effective concentrations at the tumor site. As a result, identifying BBB-penetrating drugs and utilizing new and safer methods to enhance drug delivery past the BBB has become an area of intensive research. Repurposing and combining FDA-approved drugs with evidence of penetration into the central nervous system (CNS) has also seen new interest for the treatment of both primary and recurrent GBM. In this review, we discuss emerging methods to strategically enhance drug delivery to GBM and repurpose currently-approved and previously-studied drugs using rational combination strategies.

Keywords: Blood-brain barrier; GBM; glioblastoma; pharmacotherapy; recurrent GBM; repurposed drugs.

Figure 1

Critical signaling networks in GBM that have druggable targets. All indicated drugs (boxed) exhibit current/former FDA-approval status, established BBB-penetrance, and evidence targeting GBM survival in vitro and in vivo. IRS1, Insulin receptor substrate 1; PI3K, Phosphatidylinositol-4,5-bisphosphate 3-kinase; PYK2, Protein tyrosine kinase 2; RAC1, Ras-related C3 botulinum toxin substrate 1; NFκB, Nuclear factor kappa-light-chain-enhancer of activated B cells; STAT5, Signal transducer and activator of transcription 5; TSC, Tuberous Sclerosis Complex; AMPK, AMP-activated protein kinase; ALDH, Acetaldehyde dehydrogenase.