Onto better TRAILs for cancer treatment
D de Miguel1,2, J Lemke3, A Anel1,2
1Departamento de Bioquímica, Biología Molecular y Celular, Facultad de Ciencias, Universidad de Zaragoza, Zaragoza, Spain.
Abstract:
Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a member of the TNF cytokine superfamily. By cross-linking TRAIL-Receptor (TRAIL-R) 1 or TRAIL-R2, also known as death receptors 4 and 5 (DR4 and DR5), TRAIL has the capability to induce apoptosis in a wide variety of tumor cells while sparing vital normal cells. The discovery of this unique property among TNF superfamily members laid the foundation for testing the clinical potential of TRAIL-R-targeting therapies in the cancer clinic. To date, two of these therapeutic strategies have been tested clinically: (i) recombinant human TRAIL and (ii) antibodies directed against TRAIL-R1 or TRAIL-R2. Unfortunately, however, these TRAIL-R agonists have basically failed as most human tumors are resistant to apoptosis induction by them. It recently emerged that this is largely due to the poor agonistic activity of these agents. Consequently, novel TRAIL-R-targeting agents with increased bioactivity are currently being developed with the aim of rendering TRAIL-based therapies more active. This review summarizes these second-generation novel formulations of TRAIL and other TRAIL-R agonists, which exhibit enhanced cytotoxic capacity toward cancer cells, thereby providing the potential of being more effective when applied clinically than first-generation TRAIL-R agonists.
Insights
Novel TRAIL-R agonists show enhanced cancer cell killing. Second-generation therapies aim to overcome resistance to first-generation Tumor Necrosis Factor (TNF)-related apoptosis-inducing ligand (TRAIL) treatments.
Area of Science:
- Oncology
- Immunology
- Molecular Biology
Background:
- Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) targets TRAIL-Receptor (TRAIL-R) 1/2 (DR4/DR5) to induce cancer cell apoptosis.
- TRAIL's potential in cancer therapy is limited by tumor resistance to first-generation agonists.
- Resistance is attributed to the poor agonistic activity of existing TRAIL-R-targeting agents.
Purpose of the Study:
- To review second-generation TRAIL-R agonists with improved bioactivity.
- To highlight novel formulations designed to enhance cytotoxic capacity against cancer cells.
- To assess the potential clinical efficacy of these advanced TRAIL-based therapies.
Main Methods:
- Review of current literature on TRAIL and TRAIL-R agonist therapies.
- Analysis of mechanisms underlying resistance to first-generation TRAIL-R agonists.
- Summary of development and preclinical/clinical data for second-generation TRAIL-R agonists.
Main Results:
- First-generation TRAIL-R agonists (recombinant TRAIL, anti-TRAIL-R antibodies) have shown limited clinical success due to poor efficacy.
- Tumor resistance is a major hurdle, linked to insufficient agonistic activity of initial therapeutic agents.
- Second-generation TRAIL-R agonists demonstrate enhanced cytotoxic effects and improved bioactivity in preclinical models.
Conclusions:
- Novel TRAIL-R agonists offer a promising strategy to overcome resistance in cancer therapy.
- Enhanced bioactivity of second-generation agents could lead to more effective clinical outcomes.
- Further development of these advanced TRAIL-based therapies is warranted for improved cancer treatment.
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