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

Abstract

Glioblastoma multiforme, due to 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 faced by cancer researchers is to effectively deliver drugs to invasive glioma cells residing in a sanctuary within the central nervous system. The blood–brain barrier (BBB) restricts 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, which transport drugs out of the brain back into the blood. Current clinical assessment of drug delivery and hence efficacy is based on the measured drug levels in the bulk tumor 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 tumor. Effective delivery of chemotherapeutics to the invasive glioma cells is therefore critical, and long-term efficacy will depend upon 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–tumor-cell barrier, a barrier due to expression of efflux transporters in tumor cells, that together can significantly influence drug response. It then discusses the special challenge of glioma as a disease of the whole brain, which lends particular emphasis to the need to effectively deliver drugs across the BBB to reach both the central tumor and the invasive glioma cells.

Distribution of the Phosphatidylinositol 3-Kinase Inhibitors Pictilisib (GDC-0941) and GNE-317 in U87 and GS2 Intracranial Glioblastoma Models—Assessment by Matrix-Assisted Laser Desorption Ionization Imaging

“…Our findings also support what had been hypothesized regarding the regional drug delivery in glioma (Agarwal et al, 2011) and confirm that meaningful clinical benefit, and reliable assessment of pharmacodynamics (biological) hypotheses, will most likely be achieved in GBM (or brain metastases) only with compounds able to distribute throughout the whole brain.…”

Pharmacokinetic Assessment of Efflux Transport in Sunitinib Distribution to the Brain

“…Gliomas are fatal brain tumors characterized by a high degree of microvascular proliferation with endothelial cell migration. A highly invasive tumor, the cells have a strong tendency to migrate in other parts of the brain and hide behind an intact BBB (Agarwal et al, 2011b). It is therefore important to achieve adequate drug concentrations across the BBB, in the brain parenchyma, to target the tumor cells that reside in the growing edge of the tumor as well as in the distant sites of the brain.…”

“…The core, visualized by magnetic resonance imaging, is often removed during resection; however, the tumor cells adjacent to the core are found in regions with a relatively intact BBB, and are capable of causing tumor recurrence. Furthermore, some tumor cells infiltrate into distant sites of the brain to form a sanctuary of tumor cells, thus making GBM, in essence, a "whole brain" disease (Agarwal et al, 2011b). The tumor and BBB characteristics work in tandem to present a real challenge in achieving adequate drug delivery throughout the brain, which would yield a treatment that will be most likely to result in a longer progression-free survival in GBM (Agarwal et al, 2011b).…”

ABCB1, ABCG2, and PTEN Determine the Response of Glioblastoma to Temozolomide and ABT-888 Therapy

“…Of all efflux transporters present in the BBB, ABCB1 (also known as P-glycoprotein; P-gp or MDR1) and ABCG2 (breast cancer resistance protein, BCRP) are dominant (14). Together, they are responsible for the efflux of a wide range of therapeutic agents, including many of the small molecule inhibitors that are currently under (clinical) investigation for brain cancer (15,16). Moreover, ABCB1 and ABCG2 have established roles in conferring multidrug resistance by limiting intracellular drug accumulation in tumor cells (17,18).…”