Delivery of molecularly targeted therapy to malignant glioma, a disease of the whole brain

Abstract

Glioblastoma multiforme, because of its invasive nature, can be considered a disease of the entire brain. Despite recent advances in surgery, radiotherapy and chemotherapy, current treatment regimens have only a marginal impact on patient survival. A crucial challenge is to deliver drugs effectively to invasive glioma cells residing in a sanctuary within the central nervous system. The blood-brain barrier (BBB) restricts the delivery of many small and large molecules into the brain. Drug delivery to the brain is further restricted by active efflux transporters present at the BBB. Current clinical assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumour mass that is usually removed by surgery. Mounting evidence suggests that the inevitable relapse and lethality of glioblastoma multiforme is due to a failure to effectively treat invasive glioma cells. These invasive cells hide in areas of the brain that are shielded by an intact BBB, where they continue to grow and give rise to the recurrent tumour. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore critical, and long-term efficacy will depend on the ability of a molecularly targeted agent to penetrate an intact and functional BBB throughout the entire brain. This review highlights the various aspects of the BBB, and also the brain-tumour-cell barrier (a barrier due to expression of efflux transporters in tumour cells), that together can significantly influence drug response. It then discusses the challenge of glioma as a disease of the whole brain, which lends emphasis to the need to deliver drugs effectively across the BBB to reach both the central tumour and the invasive glioma cells.

Figure 1. Molecularly Targeted Therapy for Malignant Glioma

Several signaling pathways are aberrantly activated in glioma, the most common being signaling through EGFR, PDGFR, VEGFR and c-Kit (Ref. 24). These pathways can be deregulated due to one or more mechanisms such as auto-activation, aberrant expression, mutations and decreased activity of phosphatases that turn off the signal. Signaling through these pathways can be shut down by targeted therapies that inhibit these receptors, thereby preventing the downstream effects that ultimately lead to growth and proliferation of the tumor. Such molecularly targeted therapeutic agents have been shown in the figure near the targets that they inhibit. EGFR – epidermal growth factor receptor; PDGFR – platelet derived growth factor receptor; VEGFR – vascular endothelial growth factor receptor; mTOR – mammalian target of rapamycin; PI3K – phosphatidylinositol 3-kinase; ERK - extracellular signal-regulated kinase/mitogen activated protein kinase (MAPK); MEK –mitogen-activated protein kinase kinase; SRC - rous sarcoma oncogene cellular homolog; PI3K -phosphoinositide 3-kinase; AKT - AKT8 virus oncogene cellular homolog

Figure 2. Hypothetical Schematic of Regional Drug Delivery in Glioma due to Invasive Nature of the Tumor

(A) Schematic of a brain tumor with a simulated gradient of drug concentration around the site of tumor. The tumor core, the area with a disrupted BBB, can have high drug levels (region ‘1’); however areas immediately surrounding the core can receive significantly less drug owing to an intact blood-brain barrier. (B) The tumor core is usually removed after surgery (up to boundary ‘2’); however, glioma cells invade areas of restricted drug delivery away from the tumor (regions ‘3-5’). These areas away from the tumor are the sites where the invasive glioma cells continue to grow and give rise to the recurrent tumor. (C) The goal of chemotherapy should be to effectively deliver drug in areas that can harbor the invasive glioma cells and not just the tumor core, the part of the tumor removed by surgery.

Figure 3. Multiple Mechanisms and Barriers That Limit Drug Delivery to Glioma

The blood-brain barrier and the brain-tumor cell barrier form sequential barriers that a systemically administered drug must cross to reach the tumor. A) The BBB is often disrupted at the site of the tumor allowing for easy diffusion of drugs and small molecules into the tumor. However this is also the part of the tumor that gets removed after surgery. B) The BBB however is intact in areas centimetres away from the tumor core. Drug delivery across this barrier is restricted by the presence of tight junctions between endothelial cells and more importantly by drug efflux transporters that pump drugs back into the blood. Drug that gets across this barrier and reaches the brain is usually a fraction of what reaches the tumor core. C) Invasion of glioma cells from the tumor core into the normal brain parenchyma. These small nests of tumor cells are protected by the intact BBB and receive only a small amount of drug. These cells eventually give rise to the recurrent tumor after surgery D) The brain-tumor cell barrier represents the barrier between the brain parenchyma and the tumor cell. Drug efflux transporters present in the tumor cell are a major component of this barrier and restrict intracellular drug uptake. This second barrier is especially important for molecularly targeted agents since they target intracellular domains of receptor tyrosine kinases. Pgp – p-glycoprotein; BCRP –breast cancer resistance protein; MRP – multidrug resistance associated protein.