Overcoming TRAIL Resistance for Glioblastoma Treatment

Abstract

The tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) shows a promising therapeutic potential in cancer treatment as it exclusively causes apoptosis in a broad spectrum of cancer cells through triggering the extrinsic apoptosis pathway via binding to cognate death receptors, with negligible toxicity in normal cells. However, most cancers, including glioblastoma multiforme (GBM), display TRAIL resistance, hindering its application in clinical practice. Recent studies have unraveled novel mechanisms in regulating TRAIL-induced apoptosis in GBM and sought effective combinatorial modalities to sensitize GBM to TRAIL treatment, establishing pre-clinical foundations and the reasonable expectation that the TRAIL/TRAIL death receptor axis could be harnessed to treat GBM. In this review, we will revisit the status quo of the mechanisms of TRAIL resistance and emerging strategies for sensitizing GBM to TRAIL-induced apoptosis and also discuss opportunities of TRAIL-based combinatorial therapies in future clinical use for GBM treatment.

DR5-Selective TRAIL Variant DR5-B Functionalized with Tumor-Penetrating iRGD Peptide for Enhanced Antitumor Activity against Glioblastoma

“…Glioblastoma multiforme is a highly malignant primary brain tumor, which is considered resistant to wild type TRAIL [ 27 ]. However, recent encouraging studies with different compounds, which regulate the components of the TRAIL-dependent apoptotic signaling mechanism, show that targeting the TRAIL pathway is a promising therapeutic strategy for glioblastoma treatment [ 28 ]. Despite that several dozens of TRAIL-based fusion proteins were developed in the past few years, few of them are developed for brain tumor targeting, with the blood-brain barrier (BBB) being one of the important obstacles to the implementation of TRAIL-based preparations for the treatment of glioblastoma.…”

Induction of DR5-Dependent Apoptosis by PGA2 through ATF4-CHOP Pathway

“…However, some cancers develop TRAIL resistance by downregulating the expression of death receptors or upregulating decoy receptors which hinders the binding of TRAIL to death receptors [26]. Thus, molecules that increase the expression of death receptors may have the potential to overcome TRAIL resistance [27,28]. As shown in Figure S5, PGA 2 pretreatment significantly potentiated TRAIL-induced apoptosis in HCT116 p53 −/− cells as well as HCT116 cells.…”

Application of Mesenchymal Stem Cells in Targeted Delivery to the Brain: Potential and Challenges of the Extracellular Vesicle-Based Approach for Brain Tumor Treatment

“…For brain tumors, most preclinical studies exploit MSCs as a vehicle to deliver a wide range of therapeutic agents such as chemotherapeutic drugs [ 52 ], cytokines to stimulate immune responses against tumors [ 53 ] or to inhibit angiogenesis [ 54 ], molecules to induce apoptotic processes [ 55 , 56 ], enzymes for suicide gene therapy [ 57 ], oncolytic viruses [ 58 ], etc. The two most successful strategies in terms of advancement to clinical trials are those using allogeneic BM-MSCs to deliver oncolytic adenoviruses (NCT03896568) and deliver suicide genes (NCT04657315) to treat glioblastomas.…”

“…Targeted delivery of tumor necrosis factor-related apoptosis-inducing ligands (TRAILs) is another feasible application of MSCs in glioblastoma [ 56 ] and medulloblastoma [ 55 ]. These special molecules can bind to native receptors on the target cell surface to effectively activate apoptotic pathways and cause cell death.…”