title: hvTRA, a novel TRAIL receptor agonist, induces apoptosis and sustained growth retardation in melanoma.
abstract: In recent years, new treatment options for malignant melanoma patients have enhanced the overall survival for selected patients. Despite new hope, most melanoma patients still relapse with drug-resistant tumors or experience intrinsic resistance to the therapy. Therefore, novel treatment modalities beneficial for subgroups of patients are needed. TRAIL receptor agonists have been suggested as promising candidates for use in cancer treatment as they preferentially induce apoptosis in cancer cells. Unfortunately, the first generation of TRAIL receptor agonists showed poor clinical efficacy. hvTRA is a second-generation TRAIL receptor agonist with improved composition giving increased potency, and in the present study, we showed hvTRA-induced activation of apoptosis leading to an efficient and sustained reduction in melanoma cell growth in cell lines and xenograft models. Furthermore, the potential of hvTRA in a clinical setting was demonstrated by showing efficacy on tumor cells harvested from melanoma patients with lymph node metastasis in anex vivodrug sensitivity assay. Inhibition of mutated BRAF has been shown to regulate proteins in the intrinsic apoptotic pathway, making the cells more susceptible for apoptosis induction. In an attempt to increase the efficacy of hvTRA, combination treatment with the mutated BRAF inhibitor vemurafenib was investigated. A synergistic effect by the combination was observed for several cell linesin vitro, and an initial cytotoxic effect was observedin vivo. Unfortunately, the initial increased reduction in tumor growth compared with hvTRA mono treatment was not sustained, and this was related to downregulation of the DR5 level by vemurafenib. Altogether, the presented data imply that hvTRA efficiently induce apoptosis and growth delay in melanoma models and patient material, and the potential of this TRAIL receptor agonist should be further evaluated for treatment of subgroups of melanoma patients.
authors.affiliation: Department of Tumor Biology, Oslo University Hospital, The Norwegian Radium Hospital , Oslo, Norway.
authors.forename: Karianne G
authors.initials: KG
authors.lastname: Fleten
authors.affiliation: Department of Pathology, Oslo University Hospital, The Norwegian Radium Hospital , Oslo, Norway.
authors.forename: Vivi Ann
authors.initials: VA
authors.lastname: Flørenes
authors.affiliation: Department of Tumor Biology, Oslo University Hospital, The Norwegian Radium Hospital , Oslo, Norway.
authors.forename: Lina
authors.initials: L
authors.lastname: Prasmickaite
authors.affiliation: Apogenix GmbH, Im Neuenheimer Feld , Heidelberg, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Hill
authors.affiliation: Apogenix GmbH, Im Neuenheimer Feld , Heidelberg, Germany.
authors.forename: Jaromir
authors.initials: J
authors.lastname: Sykora
authors.affiliation: Department of Tumor Biology, Oslo University Hospital, The Norwegian Radium Hospital, Oslo, Norway; Department of Pharmacy, Faculty of Health Sciences, University of Tromsø, Tromsø, Norway.
authors.forename: Gunhild M
authors.initials: GM
authors.lastname: Mælandsmo
authors.affiliation: Department of Tumor Biology, Oslo University Hospital, The Norwegian Radium Hospital , Oslo, Norway.
authors.forename: Birgit
authors.initials: B
authors.lastname: Engesæter