Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2016 May;23(5):733-47.
doi: 10.1038/cdd.2015.174. Epub 2016 Mar 4.

Onto better TRAILs for cancer treatment

D de Miguel  1   2 , J Lemke  3 , A Anel  1   2 , H Walczak  3 , L Martinez-Lostao  1   2   4
Affiliations
Review

Onto better TRAILs for cancer treatment

D de Miguel et al. Cell Death Differ. 2016 May.

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.

PubMed Disclaimer

Conflict of interest statement

AA and LM-L have filed a patent application (W02011020933) for the use of liposome-bound Apo2L/TRAIL. HW is a co-founder and shareholder of Apogenix GmbH, Heidelberg, Germany, and a named inventor on the patent that underlies the development of the TRAIL-R2-specific antibody Conatumumab. The remaining authors declare no conflict of interest.

Figures

Figure 1
Figure 1
TRAIL formulations with increased bioactivity for cancer treatment. Different formulations of TRAIL using distinct experimental approaches have been developed to increase its therapeutic potential. These formulations are mainly based in fusion proteins with single-chain variable antibody fragments (scFv), conjugation with nanoparticles and, cell-based methods to express and/or secrete Apo2L/TRAIL. The main properties improved with these highly bioactive formulations are the increase of the molecule stability, tumor targeting and the possibility of combination with other antitumor agents in a unique formulation. References: 1: leucine zipper-TRAIL;, 2: Isoleucine zipper-TRAIL homotrimer; 3: PEG-HZ-TRAIL;, 4: APG350; 5: Fn14:TRAIL;, 6: TRAIL HSA-NPs; 7: PEG-TRAIL microspheres;, 8: TRAIL-PEG-NPs; 9: TRAIL-LPs;, , 10: PEG-TRAIL/Dox microspheres; 11: TRAIL/Dox HSA-NPs; 12: magnetic NPs-TRAIL; 13: LUV-TRAIL;, , , 14: LUV-Apo2L.0; 15: sTRAIL-targeted stealth liposome; 16: TRAIL/Tf/Dox HSA-NPs; 17: immuno-LipoTRAIL; 18: Anti-CD3:TRAIL K12:TRAIL; 19: leukocytes coated with LUV-TRAIL-ES; 20: granulocytes coated with CLL1:TRAIL; 21: MBOS4:TRAIL; 22: scFv425:sTRAIL;, 23: scFvCD19:sTRAIL; 24: DbαEGFR-scTRAIL; 25: scFvCD33:sTRAIL; 26: Anti-MCSP:TRAIL; 27: scFv-EHD2-scTRAIL; 28: scFvG28:TRAILmutRs; 29: scFvCD70:TRAILmutRs; 30: RGD-L-TRAIL; 31: CD40ed:TRAILed; 32: MSC.scFvCD20-sTRAIL; 33: ANG-CLP/PTX/pEGFP-hTRAIL; 34: sTRAIL-expressing E. coli DH5α
Figure 2
Figure 2
Main effects of nanoparticle-based formulations of TRAIL. Different formulations of TRAIL using nanoparticle-based methods have been recently developed, including liposomes. These experimental approaches show a variety of advantages that help to improve the therapeutic potential of TRAIL in cancer. Conjugation with nanoparticles increases the stability of TRAIL therefore increasing its half-life and allowing a sustained release in the tumor. The so-called enhanced permeability and retention (EPR) effect allows the nanoparticles to be more specific targeting tumors than the antitumor molecules alone. This passive targeting may be improved including different molecules in the nanoparticle composition that specifically target them to the tumor. Finally, nanoparticles loaded with other drugs than TRAIL, which specifically sensitize tumor cells to TRAIL and enhance its pro-apoptotic effect, may have a synergistic effect killing tumor cells
See this image and copyright information in PMC

References

    1. Melero I, Berman DM, Aznar MA, Korman AJ, Gracia JLP, Haanen J. Evolving synergistic combinations of targeted immunotherapies to combat cancer. Nat Rev Cancer 2015; 15: 457–472. - PubMed
    1. Bracci L, Schiavoni G, Sistigu A, Belardelli F. Immune-based mechanisms of cytotoxic chemotherapy: implications for the design of novel and rationale-based combined treatments against cancer. Cell Death Differ 2014; 21: 15–25. - PMC - PubMed
    1. Kaufmann T, Simon HU. Targeting disease by immunomodulation. Cell Death Differ 2015; 22: 185–186. - PMC - PubMed
    1. Bremer E, de Bruyn M, Wajant H, Helfrich W. Targeted cancer immunotherapy using ligands of the tumor necrosis factor super-family. Curr Drug Targets 2009; 10: 94–103. - PubMed
    1. Gasparini C, Vecchi Brumatti L, Monasta L, Zauli G. TRAIL-based therapeutic approaches for the treatment of pediatric malignancies. Curr Med Chem 2013; 20: 2254–2271. - PubMed

Publication types

MeSH terms

Substances