Using gene therapy to circumvent limitations of TRAIL-based cancer therapy

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL), also known as Apo-2 ligand (Apo2L), is a 20-kDa type II transmembrane protein that belongs to the TNF superfamily. TRAIL activates apoptotic cell death through binding to DR5 receptors and caspase signaling cascade 3/7. As a death ligand, TRAIL induces apoptosis in transformed cells but shows low or no toxicity in normal cells.1Martinez-Lostao L. Marzo I. Anel A. Naval J. Targeting the Apo2L/TRAIL system for the therapy of autoimmune diseases and cancer.Biochem. Pharmacol. 2012; 83: 1475-1483Crossref PubMed Scopus (41) Google Scholar In fact, TRAIL expressed on immune cells plays important roles immunosurveillance of tumor cells.2Pimentel J.M. Zhou J.Y. Wu G.S. The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer.Cancers. 2023; 15: 2752Crossref PubMed Scopus (17) Google Scholar For these reasons, the specific cancer-targeting capability of TRAIL has attracted major interest in oncology as a potential candidate for cancer therapy. Unfortunately, there are several barriers to the use of TRAIL-based cancer therapy.3Herbst R.S. Eckhardt S.G. Kurzrock R. Ebbinghaus S. O'Dwyer P.J. Gordon M.S. Novotny W. Goldwasser M.A. Tohnya T.M. Lum B.L. et al.Phase I dose-escalation study of recombinant human Apo2L/TRAIL, a dual proapoptotic receptor agonist, in patients with advanced cancer.J. Clin. Oncol. 2010; 28: 2839-2846Crossref PubMed Scopus (381) Google Scholar,4Lemke J. von Karstedt S. Zinngrebe J. Walczak H. Getting TRAIL back on track for cancer therapy.Cell Death Differ. 2014; 21: 1350-1364Crossref PubMed Scopus (385) Google Scholar,5Brin E. Wu K. Dagostino E. Meng-Chiang Kuo M. He Y. Shia W.J. Chen L.C. Stempniak M. Hickey R. Almassy R. et al.TRAIL stabilization and cancer cell sensitization to its proapoptotic activity achieved through genetic fusion with arginine deiminase.Oncotarget. 2018; 9: 36914-36928Crossref PubMed Scopus (13) Google Scholar TRAIL itself has a very short half-life, which limits its therapeutic potential and pharmaceutical application. Recombinant TRAIL-based therapeutics exhibit low apoptotic potency, which is due to the inability of TRAIL to form native homotrimer complexes. TRAIL-based therapeutics exhibit low stability and accelerated aggregation at high concentrations, which limit drug dosages and cause adverse effects in clinical studies. Furthermore, TRAIL resistance can occur due to low expression of DR4/5, downregulation of pro-apoptotic proteins, and upregulation of apoptosis suppressors. In a recent article published in Molecular Therapy Oncology, "Targeted treatment of chondrosarcoma with a bacteriophage-based particle delivering a secreted tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)," the authors utilized a novel bacteriophage-derived particle (RGD4C.PDP-sTRAIL) to selectively deliver to tumor cells the transgene encoding a secreted TRAIL, effectively causing suicide and fratricide of surrounding tumor cells. They targeted tumors by displaying on the surface of bacteriophage (phage)-derived particles (PDPs) five copies of the tumor-targeting double cyclic CDCRGDCFC (RGD4C) ligand, which bind specifically to αvβ3 or αvβ5 integrin receptors on cancer cells and neoendothelial cells. RGD4C.PDP also displays the endosomal escape peptide to enhance gene delivery. In vitro, they detected high expression of TRAIL receptor 2/DR5 on human chondrosarcoma cells (99.8%) but not normal human articular chondrocytes (2.32%), making chondrosarcoma a particularly suitable target for TRAIL-based therapy. They demonstrated that RGD4C.PDP-sTRAIL selectively induced transgene expression in human chondrosarcoma tumors in mice and caused tumor regressions without any concerning safety signals. The results of this study indicate targeted expression of secreted TRAIL may be a promising treatment for chondrosarcoma and other TRAIL-sensitive cancers, The wider implication of the study is that TRAIL expression via gene therapy can overcome many of the limitations of recombinant TRAIL therapeutics by avoiding dose and solubility issues and achieving high local intratumoral concentrations. I have no conflicts of interest to disclose. Targeted treatment of chondrosarcoma with a bacteriophage-based particle delivering a secreted tumor necrosis factor-related apoptosis-inducing ligandChongchai et al.Molecular Therapy OncologyApril 23, 2024In BriefHajitou, Suwan, and colleagues describe a novel treatment strategy against human CS using a phage-guided gene delivery particle encoding a secreted TRAIL cytokine into the tumor microenvironment. In vitro, targeted TRAIL delivery resulted in CS cell death. In vivo, intravenous treatment inhibited CS growth and tumor viability in CS-bearing mice.