Novel approaches to combat chemoresistance against glioblastomas

Rheal A Towner,Michelle Zalles,Debra Saunders,Nataliya Smith

doi:10.20517/cdr.2020.38

Abstract

The poor prognosis of glioblastoma multiforme (GBM) patients is in part due to resistance to current standard-of-care treatments including chemotherapy [predominantly temozolomide (TMZ; Temodar)], radiation therapy and an anti-angiogenic therapy [an antibody against the vascular endothelial growth factor (bevacizumab; Avastin)], resulting in recurrent tumors. Several recurrent GBM tumors are commonly resistant to either TMZ, radiation or bevacizumab, which contributes to the low survival rate for GBM patients. This review will focus on novel targets and therapeutic approaches that are currently being considered to combat GBM chemoresistance. One of these therapeutic options is a small molecule called OKlahoma Nitrone 007 (OKN-007), which was discovered to inhibit the transforming growth factor β1 pathway, reduce TMZ-resistance and enhance TMZ-sensitivity. OKN-007 is currently an investigational new drug in clinical trials for both newly-diagnosed and recurrent GBM patients. Another novel target is ELTD1 (epidermal growth factor, latrophilin and seven transmembrane domain-containing protein 1; alternatively known as ADGRL4, Adhesion G protein-coupled receptor L4), which we used a monoclonal antibody against, where a therapy against it was found to inhibit Notch 1 in a pre-clinical GBM xenograft model. Notch 1 is known to be associated with chemoresistance in GBM. Other potential therapeutic targets to combat GBM chemoresistance include the phosphoinositide 3-kinase pathway, nuclear factor-κB, the hepatocyte/scatter factor (c-MET), the epidermal growth factor receptor, and the tumor microenvironment.

Highlights

Glioblastoma (GBM) is a devastating primary brain cancer that has a poor prognosis for patients due to limited treatment options
The major chemotherapeutic drug used for GBM is temozolomide (TMZ), and TMZ-resistance is a major reason for tumor recurrence following standard-of-care therapies [surgical resection, radiation therapy, chemotherapy, followed by an anti-angiogenic antibody against vascular endothelial growth factor (VEGF), known as bevacizumab or Avastin]
Common gene mutations associated with GBM include, epidermal growth factor receptor (EGFR)[6], IDH1[7], PDGFRA[8,9,10], HDM2[11,12,13], PIK3CA[14,15], TERT[16], PIK3R1[10,15], PTEN[17,18], TP53[19], CDKN2A[20,21], NF1[22], ATRX[23,24], and RB[25]

Summary

Introduction

Glioblastoma (GBM) is a devastating primary brain cancer that has a poor prognosis for patients due to limited treatment options. Common gene mutations associated with GBM include, epidermal growth factor receptor (EGFR)[6], IDH1[7], PDGFRA[8,9,10], HDM2[11,12,13], PIK3CA[14,15], TERT[16], PIK3R1[10,15], PTEN[17,18], TP53[19], CDKN2A[20,21], NF1[22], ATRX[23,24], and RB[25] Many of these have been investigated regarding therapeutic targets, efficacy results have been unfruitful in substantially increasing overall survival (OS). The other is a monoclonal antibody against a novel target, identified by bioinformatics, called ELTD1 or ADGRL4, which is currently being translated for subsequent human trials In addition to these therapeutic approaches that address chemoresistance in GBM, we will discuss recent promising therapeutic target developments by other investigators.

Objectives

Conclusion