TNF-related apoptosis-inducing ligand (TRAIL): A new path to anti-cancer therapies

Peter A. Holoch, Thomas S. Griffith

Research output: Contribution to journalReview articlepeer-review

166 Scopus citations

Abstract

Since its discovery in 1995, tumor necrosis factor-related apoptosis-inducing ligand (TRAIL), a member of the tumor necrosis factor super family, has been under intense focus because of its remarkable ability to induce apoptosis in malignant human cells while leaving normal cells unscathed. Consequently, activation of the apoptotic signaling pathway from the death-inducing TRAIL receptors provides an attractive, biologically-targeted approach to cancer therapy. A great deal of research has focused on deciphering the TRAIL receptor signaling cascade and intracellular regulation of this pathway, as many human tumor cells possess mechanisms of resistance to TRAIL-induced apoptosis. This review focuses on the current state of knowledge regarding TRAIL signaling and resistance, the preclinical development of therapies targeted at TRAIL receptors and modulators of the pathway, and the results of clinical trials for cancer treatment that have emerged from this base of knowledge. TRAIL-based approaches to cancer therapy vary from systemic administration of recombinant, soluble TRAIL protein with or without the combination of traditional chemotherapy, radiation or novel anti-cancer agents to agonistic monoclonal antibodies directed against functional TRAIL receptors to TRAIL gene transfer therapy. A better understanding of TRAIL resistance mechanisms may allow for the development of more effective therapies that exploit this cell-mediated pathway to apoptosis.

Original languageEnglish (US)
Pages (from-to)63-72
Number of pages10
JournalEuropean Journal of Pharmacology
Volume625
Issue number1-3
DOIs
StatePublished - Dec 25 2009

Bibliographical note

Funding Information:
This work was supported in part by grants CA109446 and CA110486 obtained from the National Cancer Institute , a grant from the Carver Charitable Trust , and a grant from the Iowa Centers for Enterprise (Battelle Research and Commercialization Funds Award ). The authors also wish to acknowledge Richard Williams, MD, Fadi Joudi, MD, Badri Konety, MD, and Tammy Madsen, PA for their vital roles in the Ad5-TRAIL phase I clinical trial.

Keywords

  • Apoptosis
  • Cancer immunotherapy
  • TRAIL receptor
  • Tumor necrosis factor-related apoptosis-inducing ligand

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