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 an ex vivo drug 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 lines in vitro, and an initial cytotoxic effect was observed in 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.
Highlights
Malignant melanoma is a highly metastatic disease with poor survival rate
The potential of hvTRA to reduce cell viability was examined in seven melanoma cell lines
The tumor volume in the vemurafenib and combination groups increased after seponation, while interestingly, the tumors treated with hvTRA did not start growing again until 8 days after seponation
Summary
Despite recent advancements leading to novel treatment options, such as the mutated BRAF inhibitor, vemurafenib and the immune activator, ipilimumab, there is still no curative treatment for the majority of patients with advanced disease.[1,2] New therapeutic options are of great importance in order to improve clinical outcomes. TRAIL receptor agonists (TRAs) have been suggested as promising anticancer candidates as they preferentially induce apoptosis in tumor cells, while normal cells are generally unaffected.[3,4] TRAs induce apoptosis by binding to Death Receptor 4 (DR4/TRAIL receptor-1) or Death. In contrast to the promising results obtained in preclinical models, all clinical trials trying to establish TRAs as drugs for human use have failed so far.[6,7,8,9,10,11,12,13] The reasons for the observed clinical failures of the first-generation TRAs are related to short in vivo exposure of the drug due to its fast elimination,[11] insufficient multimerization efficacy in vivo,[14] low expression of the TRAIL-receptors DR4 or DR5,15,16 loss or incomplete activation of pro-caspases 3 and 815,17,18 and upregulation of the anti-apoptotic protein Bcl-xL.[19]
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