Title:TRAIL-Based Therapeutic Approaches for the Treatment of Pediatric Malignancies
Volume: 20
Issue: 17
Author(s): C. Gasparini, L. Vecchi Brumatti, L. Monasta and G. Zauli
Affiliation:
Keywords:
Cancer, pediatric malignancies, PARAs, targeted therapies, TRAIL, TRAIL resistance.
Abstract: Tumor necrosis factor-related apoptosis inducing ligand (TRAIL) is a pro-apoptotic ligand that has shown the
exquisite ability to trigger extrinsic apoptosis in various types of cancer cells without significant toxicity toward normal
cells, when compared to other pro-apoptotic ligands such as tumor necrosis factor (TNF)α or Fas ligand. Consequently,
TRAIL-based therapies aim to trigger apoptosis in cancer cells by providing the soluble TRAIL or monoclonal antibodies
targeting the death receptors TRAIL-R1 or TRAIL-R2. In this review, we start by highlighting the relevance of the tumor
microenvironment in tumor development and elimination. We then address conventional and targeted therapeutic approaches
for cancer treatment, highlighting the mechanisms involved or targeted. We describe the extrinsic and intrinsic
pro-apoptotic pathways of TRAIL, together with the evidences for its pro-survival signaling, and with the relevance of
these pathways in therapy. Possible mechanisms of resistance to TRAIL-induced apoptosis are highlighted (i.e. c-FLIP,
Bcl-2, IAPs, p53, NF-κ B) and the rationale for the combined administration of TRAIL with drugs targeting these mechanisms
is provided. Preclinical data are reported and show encouraging evidences for TRAIL consideration in pediatric malignancies
(i.e., leukemia, lymphomas, neuroblastoma, osteosarcoma, medulloblastoma). Clinical trials of TRAIL-based
therapies on the overall population are in phase I or II, and we put particular focus on the pediatric population, on which
only few trials have been conducted or are ongoing. Finally, we consider emerging cellular therapies based on TRAIL,
such as TRAIL-engineered mesenchymal stem cells or ‘inflammatory’ dendritic cells.
