DR4 specific TRAIL variants are more efficacious than wild-type TRAIL in pancreatic cancer

Abstract

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.

Therapeutic applications of TRAIL receptor agonists in cancer and beyond

“…Unfortunately, Dulanermin did not demonstrate significant clinical efficacy when it came to complete responses, and a number of hypotheses were proposed to explain why — including short bioavailability and the potential to bind to death-inducing and — inhibiting TRAIL receptors. A variety of modified versions of TRAIL have been engineered with the intention of increasing the circulating half-life of the molecule without significantly altering function (van der Sloot et al, 2006; Tur et al, 2008; Wahl et al, 2013; Yu et al, 2014). However, these TRAIL variants have only been tested preclinically.…”

Prognostic Biomarkers for Hodgkin Lymphoma

“…Similarly, binding of TRAIL to TNFRSF10C (TRAIL receptor 3 = CD263) and TNFRSF10D (TRAIL receptor 4 = CD264) does not induce apoptosis. TRAIL mutants with increased binding affinity for the apoptosis-inducing receptors TNFRSF10A (TRAIL receptor 1 = CD261) and TNFRSF10B (TRAIL receptor 2 = CD262) have been generated and might be interesting for tumor therapy [64]. Binding of TRAIL on the surface of T cells to the immobilized receptor can lead to augmented T-cell activation, suggesting that TRAIL (like TNF) might have immune regulatory functions [65].…”

Targeting the death receptor signaling pathway as a potential therapeutic target in the treatment of colorectal cancer

“…New compounds have been engineered to increase the half‐life of the Dulanermin in the circulation. However, these compounds are still under investigation in pre‐clinical studies (Wahl et al, ; Yu et al, ).…”