Dr4 specific trail variants are more efficacious than wild-type trail in pancreatic cancer
Albarenque, Stella Maris
Cool, Robbert H
Quax, Wim J
Zwacka, Ralf M
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Yu, Rui; Albarenque, Stella Maris; Cool, Robbert H; Quax, Wim J; Mohr, Andrea; Zwacka, Ralf M (2014). Dr4 specific trail variants are more efficacious than wild-type trail in pancreatic cancer. Cancer Biology & Therapy 15 (12), 1658-1666
Current treatment modalities for pancreatic carcinoma afford only modest survival benefits. TRAIL, as a potent and specific inducer of apoptosis in cancer cells, would be a promising new treatment option. However, since not all pancreatic cancer cells respond to TRAIL, further improvements and optimizations are still needed. One strategy to improve the effectiveness of TRAIL-based therapies is to specifically target one of the 2 cell death inducing TRAIL-receptors, TRAIL-R1 or TRAIL-R2 to overcome resistance. To this end, we designed constructs expressing soluble TRAIL (sTRAIL) variants that were rendered specific for either TRAIL-R1 or TRAIL-R2 by amino acid changes in the TRAIL ectodomain. When we expressed these constructs, including wild-type sTRAIL (sTRAIL(wt)), TRAIL-R1 (sTRAIL(DR4)) and TRAIL-R2 (sTRAIL(DR5)) specific variants, in 293 producer cells we found all to be readily expressed and secreted into the supernatant. These supernatants were subsequently transferred onto target cancer cells and apoptosis measured. We found that the TRAIL-R1 specific variant had higher apoptosis-inducing activity in human pancreatic carcinoma Colo357 cells as well as PancTu1 cells that were additionally sensitized by targeting of XIAP. Finally, we tested TRAIL-R1 specific recombinant TRAIL protein (rTRAIL(DR4)) on Colo357 xenografts in nude mice and found them to be more efficacious than rTRAIL(wt). Our results demonstrate the benefits of synthetic biological approaches and show that TRAIL-R1 specific variants can potentially enhance the therapeutic efficacy of TRAIL-based therapies in pancreatic cancer, suggesting that they can possibly become part of individualized and tumor specific combination treatments in the future.
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Rapid and efficient cancer cell killing mediated by high-affinity death receptor homotrimerizing trail variants Reis, C R; van der Sloot, A M; Natoni, A; Szegezdi, E; Setroikromo, R; Meijer, M; Sjollema, K; Stricher, F; Cool, R H; Samali, A; Serrano, L; Quax, W J (Springer Nature, 2010-10-01)The tumour necrosis factor family member TNF-related apoptosis-inducing ligand (TRAIL) selectively induces apoptosis in a variety of cancer cells through the activation of death receptors 4 (DR4) and 5 (DR5) and is considered ...
Targeting of xiap combined with systemic mesenchymal stem cell-mediated delivery of strail ligand inhibits metastatic growth of pancreatic carcinoma cells Mohr, Andrea; Albarenque, Stella Maris; Deedigan, Laura; Yu, Rui; Reidy, Mairead; Fulda, Simone; Zwacka, Ralf Michael (Wiley-Blackwell, 2010-11-01)Disseminating tumors are one of the gravest medical problems. Here, we combine the tumor-specific apoptosis-inducing activity of tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) with the ability of mesenchymal ...
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