Targeting core (mutated) pathways of high-grade gliomas: challenges of intrinsic resistance and drug efflux

Abstract

High-grade gliomas are the most common type of primary brain tumor and are among the most lethal types of human cancer. Most patients with a high-grade glioma have glioblastoma multiforme (GBM), the most malignant glioma subtype that is associated with a very aggressive disease course and short overall survival. Standard treatment of newly diagnosed GBM involves surgery followed by chemoradiation with temozolomide. However, despite this extensive treatment the mean overall survival is still only 14.6 months and more effective treatments are urgently needed. Although different types of GBMs are indistinguishable by histopathology, novel molecular pathological techniques allow discrimination between the four main GBM subtypes. Targeting the aberrations in the molecular pathways underlying these subtypes is a promising strategy to improve therapy. In this article, we will discuss the potential avenues and pitfalls of molecularly targeted therapies for the treatment of GBM.

ABCB1 and ABCG2 restrict the brain penetration of a panel of novel EZH2‐Inhibitors

“…Elacridar is also used in many preclinical studies to demonstrate the impact of Abcb1a/1b and Abcg2 on the brain accumulation of drugs. 31 Elacridar, however, was not potent enough to block murine Abcg2 mediated transport of EPZ005687, UNC1999 and GSK343. When given together with Ko143, a specific ABCG2/Abcg2 inhibitor, all directional translocation was abolished.…”

“…In our in vitro experiments, elacridar has been utilized as a dual inhibitor of ABCB1 and ABCG2. Elacridar is also used in many preclinical studies to demonstrate the impact of Abcb1a/1b and Abcg2 on the brain accumulation of drugs . Elacridar, however, was not potent enough to block murine Abcg2 mediated transport of EPZ005687, UNC1999 and GSK343.…”

P-glycoprotein and breast cancer resistance protein restrict the brain penetration of the CDK4/6 inhibitor palbociclib

“…However, in many cases trans-cellular entry of such compounds into the brain is restricted by the action of ATPbinding cassette (ABC) transporters expressed at the apical membrane of the microvascular endothelium in the brain. Of these, P-glycoprotein (P-gp/ABCB1) and Breast Cancer Resistance Protein (BCRP/ABCG2) are the two dominant ABC transporters at the BBB that together restrict the brain penetration of numerous compounds [13]. Moreover, the same transport proteins are also active in the gastro-intestinal tract and involved in limiting the oral bioavailability of substrate drugs [14].…”

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).…”