title: Melanoma-associated Chondroitin Sulfate Proteoglycan (MCSP)-targeted delivery of soluble TRAIL potently inhibits melanoma outgrowth in vitro and in vivo.
abstract: BACKGROUND
  Advanced melanoma is characterized by a pronounced resistance to therapy leading to a limited patient survival of ~6 - 9 months. Here, we report on a novel bifunctional therapeutic fusion protein, designated anti-MCSP:TRAIL, that is comprised of a melanoma-associated chondroitin sulfate proteoglycan (MCSP)-specific antibody fragment (scFv) fused to soluble human TRAIL. MCSP is a well-established target for melanoma immunotherapy and has recently been shown to provide important tumorigenic signals to melanoma cells. TRAIL is a highly promising tumoricidal cytokine with no or minimal toxicity towards normal cells. Anti-MCSP:TRAIL was designed to 1. selectively accrete at the cell surface of MCSP-positive melanoma cells and inhibit MCSP tumorigenic signaling and 2. activate apoptotic TRAIL-signaling.
  
  
  RESULTS
  Treatment of a panel of MCSP-positive melanoma cell lines with anti-MCSP:TRAIL induced TRAIL-mediated apoptotic cell death within 16 h. Of note, treatment with anti-MCSP:sTRAIL was also characterized by a rapid dephosphorylation of key proteins, such as FAK, implicated in MCSP-mediated malignant behavior. Importantly, anti-MCSP:TRAIL treatment already inhibited anchorage-independent growth by 50% at low picomolar concentrations, whereas > 100 fold higher concentrations of non-targeted TRAIL failed to reduce colony formation. Daily i.v. treatment with a low dose of anti-MCSP:TRAIL (0.14 mg/kg) resulted in a significant growth retardation of established A375 M xenografts. Anti-MCSP:TRAIL activity was further synergized by co-treatment with rimcazole, a σ-ligand currently in clinical trials for the treatment of various cancers.
  
  
  CONCLUSIONS
  Anti-MCSP:TRAIL has promising pre-clinical anti-melanoma activity that appears to result from combined inhibition of tumorigenic MCSP-signaling and concordant activation of TRAIL-apoptotic signaling. Anti-MCSP:TRAIL alone, or in combination with rimcazole, may be of potential value for the treatment of malignant melanoma.
authors.affiliation: Surgical Research Laboratories, Department of Surgery, University Medical Center Groningen (Hanzeplein 1), University of Groningen, Groningen (9713 GZ), The Netherlands.
authors.forename: Marco
authors.initials: M
authors.lastname: de Bruyn
authors.forename: Anna A
authors.initials: AA
authors.lastname: Rybczynska
authors.forename: Yunwei
authors.initials: Y
authors.lastname: Wei
authors.forename: Michael
authors.initials: M
authors.lastname: Schwenkert
authors.forename: Georg H
authors.initials: GH
authors.lastname: Fey
authors.forename: Rudi A J O
authors.initials: RA
authors.lastname: Dierckx
authors.forename: Aren
authors.initials: A
authors.lastname: van Waarde
authors.forename: Wijnand
authors.initials: W
authors.lastname: Helfrich
authors.forename: Edwin
authors.initials: E
authors.lastname: Bremer
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D002478:Cells, Cultured; D011508:Chondroitin Sulfate Proteoglycans / Q000235:genetics / Q000378:metabolism*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D008297:Male; D008544:Melanocytes / Q000187:drug effects / Q000378:metabolism; D008545:Melanoma / Q000188:drug therapy* / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D020543:Proteome / Q000187:drug effects; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology / Q000627:therapeutic use*; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011508:Chondroitin Sulfate Proteoglycans; D020543:Proteome; D011993:Recombinant Fusion Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand