Targeting Tumor Necrosis Factor–Related Apoptosis-Inducing Ligand (TRAIL): A Promising Therapeutic Strategy in Gliomas George A. Alexiou, MD, PhD, * Konstantinos I. Tsamis, MD, PhD, * and Athanasios P. Kyritsis, MD, PhD *,† Tumor necrosis factor–related apoptosis-inducing ligand (TRAIL) has been increasingly studied for the treatment of gliomas. TRAIL has the ability to specifically target cancer cells, without any harmful effects on normal cells, and induces apoptosis by interacting with specific receptors. Nevertheless, resistance mechanisms to TRAIL may occur at different points in the signaling pathways of TRAIL-induced apoptosis. Various approaches have been developed to overcome TRAIL resistance. Here, we have reviewed the known molecular pathways by which TRAIL exerts anticancer activity, possible resistance mechanisms, ways to sensitize resistant cancer cells, and finally the current clinical successes or limitations of TRAIL-based therapies. Semin Pediatr Neurol 22:35-39 C 2015 Elsevier Inc. All rights reserved. Introduction Brain tumors are the second most common malignancy in children after leukemia. Astrocytomas are the most frequent tumors, with pilocytic astrocytomas accounting for approx- imately one-fourth of brain tumor cases. The second most common entity is medulloblastoma, the most aggressive pediatric brain tumor, followed by ependymomas. 1 A worrisome finding from a series of recent literature was an increase in pediatric brain tumor incidence and also a trend toward an increased incidence of tumors of higher malig- nancy, contrary to a decline of the more benign lesions such as pilocytic astrocytomas. 1,2 Gliomas are among the most common brain tumor in adults, with an incidence rate of 6.02 cases per 100,000. Glioblastoma, the most malignant brain tumor, has an incidence rate of 3.19 cases per 100,000. 3 The standard of care for high-grade gliomas is gross total excision followed by radiotherapy with concomitant and adjuvant temozolomide-based chemotherapy. Nevertheless, the average survival for patients with glioblastoma is only approximately 15 months. Therefore, new and better treat- ments are urgently needed. For nonpilocytic low-grade gliomas, survival is better, nearly 7 years. 4 Pilocytic astro- cytomas are often curable with surgery alone, if located in an accessible part of the brain. The Apoptotic Program Among the known hallmarks of cancer, induction of apoptosis is a promising therapeutic approach to eliminate cancer cells. 5 Apoptosis is a form of programmed cell death and is induced via well-characterized intrinsic and extrin- sic pathways (Fig.). The intrinsic or mitochondrial path- way is p53 dependent and is initiated in response to stress within the cell, such as DNA damage and endoplasmic reticulum stress. The mitochondrial pathway starts by alterations in mitochondrial membrane permeability. Then, there is release of cytochrome c and of the second mitochondria-derived activator of caspase (Smac)/direct inhibitor of apoptosis (IAP)–binding protein (DIABLO) into the cytosol. 6 The release of apoptotic factors from the mitochondria is controlled by the action of the proapop- totic and antiapoptotic proteins of the B-cell lymphoma 2 (Bcl-2) family. Apoptotic factors lead to cytoplasmic assembly of the apoptosome complex, a protein complex 1071-9091/14/$-see front matter & 2015 Elsevier Inc. All rights reserved. 35 http://dx.doi.org/10.1016/j.spen.2014.12.002 From the *Neurosurgical Institute, University of Ioannina School of Medicine, Ioannina, Greece. †Department of Neurology, University Hospital of Ioannina, Ioannina, Greece. Address reprint requests to George A. Alexiou, MD, PhD, PO Box 103, Neohoropoulo, Ioannina 45500, Greece. E-mail: alexiougrg@yahoo.gr, alexiougr@gmail.com