Review: on TRAIL for malignant glioma therapy?
Glioblastoma (GBM) is a devastating cancer with a median survival of around 15 months. Significant advances in treatment have not been achieved yet, even with a host of new therapeutics under investigation. Therefore, the quest for a cure for GBM remains as intense as ever. Of particular interest for GBM therapy is the selective induction of apoptosis using the pro-apoptotic tumour necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL signals apoptosis via its two agonistic receptors TRAIL-R1 and TRAIL-R2. TRAIL is normally present as homotrimeric transmembrane protein, but can also be processed into a soluble trimeric form (sTRAIL). Recombinant sTRAIL has strong tumouricidal activity towards GBM cells, with no or minimal toxicity towards normal human cells. Unfortunately, GBM is a very heterogeneous tumour, with multiple genetically aberrant clones within one tumour. Consequently, any single agent therapy is likely to be not effective enough. However, the anti-GBM activity of TRAIL can be synergistically enhanced by a variety of conventional and novel targeted therapies, making TRAIL an ideal candidate for combinatorial strategies. Here we will, after briefly detailing the biology of TRAIL/TRAIL receptor signalling, focus on the promises and pitfalls of recombinant TRAIL as a therapeutic agent alone and in combinatorial therapeutic approaches for GBM.
Kuijlen
J M A
JM
Department of Neurosurgery, University Medical Center Groningen (UMCG), University of Groningen, Groningen, The Netherlands.
Bremer
E
E
Mooij
J J A
JJ
den Dunnen
W F A
WF
Helfrich
W
W
D000818:Animals; D017209:Apoptosis / Q000235:genetics / Q000502:physiology; D005910:Glioma / Q000378:metabolism / Q000628:therapy*; D006801:Humans; D008959:Models, Neurological; D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000627:therapeutic use*
D053220:Receptors, TNF-Related Apoptosis-Inducing Ligand; D053221:TNF-Related Apoptosis-Inducing Ligand