title: A Bifunctional Approach of Immunostimulation and uPAR Inhibition Shows Potent Antitumor Activity in Melanoma.
abstract: Significant advancements of mutation-based targeted therapy and immune checkpoint blockade have been achieved in melanoma. Nevertheless, acquired resistance and nonresponders to therapy require different strategies. An innovative approach is presented here that is based on the combination of innate immune system activation and simultaneous targeting of the oncogene urokinase-type plasminogen activator receptor (uPAR). We generated two triphosphate-conjugated siRNAs targeting uPAR (ppp-uPAR) by in vitro transcription. Specific uPAR knockdown and simultaneous activation of the retinoic acid-inducible gene 1 (RIG-I) was shown in different human melanoma cells, fibroblasts, and melanocytes. The compounds induced massive apoptosis in melanoma cells, whereas fibroblasts and melanocytes were less sensitive. The effects were less pronounced when the IFN receptor was blocked. Treatment with ppp-uPAR led to accumulation of p53 and induction of RIG-I-dependent proapoptotic signaling. The apoptotic effects induced by ppp-uPAR were maintained in melanoma cell lines that had acquired double resistance to B-RAF and MEK/extracellular signal-regulated kinase inhibition. Systemic intraperitoneal application of ppp-uPAR in nude mice significantly reduced growth of human melanoma xenografts and elicited a systemic innate immune response with increased serum cytokine levels. Our data suggest that ppp-uPAR represents a therapeutically attractive compound that may help overcome the strong therapy resistance of melanoma.
authors: Department of Dermatology and Allergy, Munich University Hospital (LMU), Germany.
authors: Fanny
authors: F
authors: Matheis
authors: Department of Dermatology and Allergy, Munich University Hospital (LMU), Germany.
authors: Markus V
authors: MV
authors: Heppt
authors: Department of Dermatology and Allergy, Munich University Hospital (LMU), Germany.
authors: Saskia A
authors: SA
authors: Graf
authors: Division of Clinical Pharmacology, Department of Medicine, Ludwig-Maximilian University Munich, Germany.
authors: Peter
authors: P
authors: Düwell
authors: Department of Dermatology and Allergy, Munich University Hospital (LMU), Germany.
authors: Claudia
authors: C
authors: Kammerbauer
authors: Division of Clinical Pharmacology, Faculty of Medicine, Rudolf-Boehm-Institute of Pharmacology and Toxicology, University Leipzig, Germany.
authors: Achim
authors: A
authors: Aigner
authors: Department of Dermatology and Allergy, Munich University Hospital (LMU), Germany.
authors: Robert
authors: R
authors: Besch
authors: Department of Dermatology and Allergy, Munich University Hospital (LMU), Germany. Electronic address: Carola.Berking@med.uni-muenchen.de.
authors: Carola
authors: C
authors: Berking
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007114:Immunization / Q000379:methods*; D008544:Melanocytes / Q000166:cytology / Q000473:pathology; D008545:Melanoma / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D009419:Nerve Tissue Proteins / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics; D011897:Random Allocation; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator / Q000235:genetics*; D012016:Reference Values; D012878:Skin Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D014407:Tumor Cells, Cultured; D000097905:Roundabout Proteins
chemical_list: D008565:Membrane Proteins; D009419:Nerve Tissue Proteins; D034741:RNA, Small Interfering; D011956:Receptors, Cell Surface; D055293:Receptors, Urokinase Plasminogen Activator; C118348:Robo3 protein, mouse; D000097905:Roundabout Proteins