Novel approaches to combat chemoresistance against glioblastomas

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.

Keywords: ELTD1; Glioblastoma; OKlahoma Nitrone 007; magnetic resonance imaging; pre-clinical models; transforming growth factor-β1.

Figure 1

Stromal activators of transforming growth factor-β (TGF-β) in the tumor microenvironment. MMP2 and MMP9 proteolytically cleave latent TGF-β binding protein (LTBP), thereby releasing latent TGF-β from the extracellular matrix. MMP1A, MMP2, MMP3, MMp7, MMP8, MMP9, MMP12, MMP13 and MMP14 activate latent TGF-β via proteolytic cleavage of the latency-associated peptide (LAP), while integrins expressed on astrocytes (ITGA1, 2 and 4) bind to the large latent complex (LLC) and activate latent TGF-β through MMP-dependent cleavage of LAP. Integrins (ITGA1, 2 and 4) bind to the LLC and induce conformational changes in the latent complex via contractile action from activated astrocytes. Reactive oxygen species (ROS) produced by activated astrocytes via the induction of oxidative stress from adjacent cancer cells can lead to the oxidation of the LAP domain and induce allosteric changes that release mature TGF-β from LAP. The mature (active) form of TGF-β can then bind to its cognate receptor and exert its tumor promoting and tumor suppressive properties. Dashed arrow indicates recruitment of the mature TGF-β protein to its cognate receptor. Other tumor-associated pathways/signaling molecules include fibroblast growth factor receptor (FGFR), EGFR, mammalian target of rapamycin (mTOR)/Akt/PI3K, HIFα (hypoxia inducible factor α), β-catenin, and stat3 (signal transducer and activator of transcription 3) (via the IL-6/CNTF receptor). Modified from Costanza et al.^[104] (2017). Based on microarray and RT-PCR data from the rat F98 glioma model, comparing untreated to OKN-007-treated tumor tissue, OKN-007 is thought to act on LTBP^[40], as well as ROS^[105]. LTBP2, MMP1A, MMP2, MMP3, MMP7, MMP8, MMP9, MMP12, MMP13 and MMP14, were all found to be downregulated in microarray and/or RT-PCR data from the F98 glioma study^[40]. Modified with permission from Dr. Towner, which was originally published in Towner et al.^[40] (2019)

Figure 2

Targeting either the transforming growth factor β1 pathway or ELTD1 in pre-clinical studies for glioblastoma multiforme (GBM). OKlahoma Nitrone 007 (OKN-007) is able to significantly increase animal survival (A) or decrease tumor volumes (B) following combined OKN-007 and TMZ treatments in an orthotopic G55 GBM xenograft model. Examples of MR images from untreated (UT) (C), OKN-007- (OKN) (D), TMZ- (E), or combined (OKN-007 + TMZ) (F) treatments; a monoclonal antibody (mAb) against ELTD1 significantly increased animal survival (G) and decreased tumor volumes (H) in an orthotopic G55 GBM xenograft model; (I) Notch 1 levels were significantly decreased with a mAb against ELTD1 in a G55 GBM model. This figure was obtained from modified data with the permission of Dr. Towner, as reported in Towner et al.^[40] and Zalles et al.^[74]