TRAIL-Based Therapeutic Approaches for the Treatment of Pediatric Malignancies

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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-κB) 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.

Keywords: Cancer; PARAs; TRAIL; TRAIL resistance; pediatric malignancies; targeted therapies

Document Type: Research Article

Publication date: June 1, 2013

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  • Current Medicinal Chemistry covers all the latest and outstanding developments in medicinal chemistry and rational drug design. Each issue contains a series of timely in-depth reviews written by leaders in the field covering a range of the current topics in medicinal chemistry. Current Medicinal Chemistry is an essential journal for every medicinal chemist who wishes to be kept informed and up-to-date with the latest and most important developments.
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