Therapeutic targeting of TRAIL death receptors
Francesca Di Cristofano1,2,3,4, Andrew George1,2,3,4, Vida Tajiknia1,2,3,4
1Laboratory of Translational Oncology and Experimental Cancer Therapeutics, The Warren Alpert Medical School, Brown University, Providence, RI 02903, U.S.A.
Abstract:
The discovery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) along with its potent and selective antitumor effects initiated a decades-long search for therapeutic strategies to target the TRAIL pathway. First-generation approaches were focused on the development of TRAIL receptor agonists (TRAs), including recombinant human TRAIL (rhTRAIL) and TRAIL receptor-targeted agonistic antibodies. While such TRAIL pathway-targeted therapies showed promise in preclinical data and clinical trials have been conducted, none have advanced to FDA approval. Subsequent second-generation approaches focused on improving upon the specific limitations of first-generation approaches by ameliorating the pharmacokinetic profiles and agonistic abilities of TRAs as well as through combinatorial approaches to circumvent resistance. In this review, we summarize the successes and shortcomings of first- and second-generation TRAIL pathway-based therapies, concluding with an overview of the discovery and clinical introduction of ONC201, a compound with a unique mechanism of action that represents a new generation of TRAIL pathway-based approaches. We discuss preclinical and clinical findings in different tumor types and provide a unique perspective on translational directions of the field.
Insights
The TRAIL pathway offers potent antitumor effects. While early TRAIL receptor agonists showed promise, new strategies like ONC201 represent a next generation of cancer therapies targeting this pathway.
Area of Science:
- Oncology
- Molecular Biology
- Drug Discovery
Background:
- The discovery of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) revealed its potent and selective antitumor capabilities.
- Targeting the TRAIL pathway has been a focus for cancer therapy development for decades.
- Despite extensive research, no TRAIL pathway-targeted therapies have achieved FDA approval.
Approach:
- First-generation approaches focused on TRAIL receptor agonists (TRAs), including recombinant human TRAIL (rhTRAIL) and agonistic antibodies.
- Second-generation approaches aimed to overcome limitations of first-generation TRAs through improved pharmacokinetics, agonistic abilities, and combinatorial strategies.
- This review examines the successes and failures of these generations of TRAIL pathway-based therapies.
Key Points:
- First-generation TRAIL pathway therapies demonstrated preclinical promise but failed to gain FDA approval.
- Second-generation therapies sought to enhance efficacy and overcome resistance mechanisms.
- ONC201, a novel compound with a unique mechanism, represents a new wave of TRAIL pathway-based therapeutic strategies.
Conclusions:
- ONC201's unique mechanism signifies a new generation of TRAIL pathway-based cancer treatments.
- The review discusses preclinical and clinical findings across various tumor types.
- Future translational directions for TRAIL pathway-based therapies are explored.
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