Ligand-based targeting of apoptosis in cancer: The potential of recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL)

Avi Ashkenazi, Pamela Holland, S Gail Eckhardt

Research output: Contribution to journalReview article

322 Citations (Scopus)

Abstract

Cancer is a leading cause of premature human death and commands considerable research attention. Apoptosis (type 1 programmed cell death) is critical in maintaining tissue homeostasis in metazoan organisms, and its dysregulation underpins the initiation and progression of cancer. Conventional chemotherapy and radiotherapy can induce apoptosis as a secondary consequence of inflicting cell damage. However, more direct and selective strategies to manipulate the apoptotic process in cancer cells are emerging as potential therapeutic tools. Genetic and biochemical understanding of the cellular signaling mechanisms that control apoptosis has increased substantially during the last decade. These advances provide a strong scientific framework for developing several types of targeted proapoptotic anticancer therapies. One promising class of agents is the proapoptotic receptor agonists. Of these, recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL) - an optimized soluble form of an endogenous apoptosis-inducing ligand - is unique in that it activates two related proapoptotic receptors, DR4 and DR5. Preclinical data indicate that rhApo2L/TRAIL can induce apoptosis in a broad range of human cancer cell lines while sparing most normal cell types. In vitro, and in various in vivo tumor xenograft models, rhApo2L/TRAIL exhibits single-agent antitumor activity and/or cooperation with certain conventional and targeted therapies. Preclinical safety studies in nonhuman primates show rhApo2L/TRAIL to be well tolerated. Moreover, early clinical trial data suggest that rhApo2L/TRAIL is generally safe and provide preliminary evidence for potential antitumor activity. Clinical studies are ongoing to assess the safety and efficacy of this novel agent in combination with established anticancer therapies.

Original languageEnglish (US)
Pages (from-to)3621-3630
Number of pages10
JournalJournal of Clinical Oncology
Volume26
Issue number21
DOIs
StatePublished - Sep 15 2008

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Tumor Necrosis Factor-alpha
Apoptosis
Ligands
Neoplasms
TNF-Related Apoptosis-Inducing Ligand Receptors
Safety
Premature Mortality
Therapeutics
Heterografts
Antineoplastic Agents
Primates
Molecular Biology
Homeostasis
Radiotherapy
Clinical Trials
Drug Therapy
Cell Line
Research

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

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title = "Ligand-based targeting of apoptosis in cancer: The potential of recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL)",
abstract = "Cancer is a leading cause of premature human death and commands considerable research attention. Apoptosis (type 1 programmed cell death) is critical in maintaining tissue homeostasis in metazoan organisms, and its dysregulation underpins the initiation and progression of cancer. Conventional chemotherapy and radiotherapy can induce apoptosis as a secondary consequence of inflicting cell damage. However, more direct and selective strategies to manipulate the apoptotic process in cancer cells are emerging as potential therapeutic tools. Genetic and biochemical understanding of the cellular signaling mechanisms that control apoptosis has increased substantially during the last decade. These advances provide a strong scientific framework for developing several types of targeted proapoptotic anticancer therapies. One promising class of agents is the proapoptotic receptor agonists. Of these, recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL) - an optimized soluble form of an endogenous apoptosis-inducing ligand - is unique in that it activates two related proapoptotic receptors, DR4 and DR5. Preclinical data indicate that rhApo2L/TRAIL can induce apoptosis in a broad range of human cancer cell lines while sparing most normal cell types. In vitro, and in various in vivo tumor xenograft models, rhApo2L/TRAIL exhibits single-agent antitumor activity and/or cooperation with certain conventional and targeted therapies. Preclinical safety studies in nonhuman primates show rhApo2L/TRAIL to be well tolerated. Moreover, early clinical trial data suggest that rhApo2L/TRAIL is generally safe and provide preliminary evidence for potential antitumor activity. Clinical studies are ongoing to assess the safety and efficacy of this novel agent in combination with established anticancer therapies.",
author = "Avi Ashkenazi and Pamela Holland and Eckhardt, {S Gail}",
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T2 - The potential of recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL)

AU - Ashkenazi, Avi

AU - Holland, Pamela

AU - Eckhardt, S Gail

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N2 - Cancer is a leading cause of premature human death and commands considerable research attention. Apoptosis (type 1 programmed cell death) is critical in maintaining tissue homeostasis in metazoan organisms, and its dysregulation underpins the initiation and progression of cancer. Conventional chemotherapy and radiotherapy can induce apoptosis as a secondary consequence of inflicting cell damage. However, more direct and selective strategies to manipulate the apoptotic process in cancer cells are emerging as potential therapeutic tools. Genetic and biochemical understanding of the cellular signaling mechanisms that control apoptosis has increased substantially during the last decade. These advances provide a strong scientific framework for developing several types of targeted proapoptotic anticancer therapies. One promising class of agents is the proapoptotic receptor agonists. Of these, recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL) - an optimized soluble form of an endogenous apoptosis-inducing ligand - is unique in that it activates two related proapoptotic receptors, DR4 and DR5. Preclinical data indicate that rhApo2L/TRAIL can induce apoptosis in a broad range of human cancer cell lines while sparing most normal cell types. In vitro, and in various in vivo tumor xenograft models, rhApo2L/TRAIL exhibits single-agent antitumor activity and/or cooperation with certain conventional and targeted therapies. Preclinical safety studies in nonhuman primates show rhApo2L/TRAIL to be well tolerated. Moreover, early clinical trial data suggest that rhApo2L/TRAIL is generally safe and provide preliminary evidence for potential antitumor activity. Clinical studies are ongoing to assess the safety and efficacy of this novel agent in combination with established anticancer therapies.

AB - Cancer is a leading cause of premature human death and commands considerable research attention. Apoptosis (type 1 programmed cell death) is critical in maintaining tissue homeostasis in metazoan organisms, and its dysregulation underpins the initiation and progression of cancer. Conventional chemotherapy and radiotherapy can induce apoptosis as a secondary consequence of inflicting cell damage. However, more direct and selective strategies to manipulate the apoptotic process in cancer cells are emerging as potential therapeutic tools. Genetic and biochemical understanding of the cellular signaling mechanisms that control apoptosis has increased substantially during the last decade. These advances provide a strong scientific framework for developing several types of targeted proapoptotic anticancer therapies. One promising class of agents is the proapoptotic receptor agonists. Of these, recombinant human apoptosis ligand 2/tumor necrosis factor-related apoptosis-inducing ligand (rhApo2L/TRAIL) - an optimized soluble form of an endogenous apoptosis-inducing ligand - is unique in that it activates two related proapoptotic receptors, DR4 and DR5. Preclinical data indicate that rhApo2L/TRAIL can induce apoptosis in a broad range of human cancer cell lines while sparing most normal cell types. In vitro, and in various in vivo tumor xenograft models, rhApo2L/TRAIL exhibits single-agent antitumor activity and/or cooperation with certain conventional and targeted therapies. Preclinical safety studies in nonhuman primates show rhApo2L/TRAIL to be well tolerated. Moreover, early clinical trial data suggest that rhApo2L/TRAIL is generally safe and provide preliminary evidence for potential antitumor activity. Clinical studies are ongoing to assess the safety and efficacy of this novel agent in combination with established anticancer therapies.

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