title: Melanoma stem cells in experimental melanoma are killed by radioimmunotherapy.
abstract: BACKGROUND
  In spite of recently approved B-RAF inhibitors and immunomodulating antibodies, metastatic melanoma has poor prognosis and novel treatments are needed. Melanoma stem cells (MSC) have been implicated in the resistance of this tumor to chemotherapy. Recently we demonstrated in a Phase I clinical trial in patients with metastatic melanoma that radioimmunotherapy (RIT) with 188-Rhenium((188)Re)-6D2 antibody to melanin was a safe and effective modality. Here we investigated the interaction of MSC with RIT as a possible mechanism for RIT efficacy.
  
  
  METHODS
  Mice bearing A2058 melanoma xenografts were treated with either 1.5 mCi (188)Re-6D2 antibody, saline, unlabeled 6D2 antibody or (188)Re-labeled non-specific IgM.
  
  
  RESULTS
  On Day 28 post-treatment the tumor size in the RIT group was 4-times less than in controls (P<0.001). The tumors were analyzed by immunohistochemistry and FACS for two MSC markers--chemoresistance mediator ABCB5 and H3K4 demethylase JARID1B. There were no significant differences between RIT and control groups in percentage of ABCB5 or JARID1B-positive cells in the tumor population. Our results demonstrate that unlike chemotherapy, which kills tumor cells but leaves behind MSC leading to recurrence, RIT kills MSC at the same rate as the rest of tumor cells.
  
  
  CONCLUSIONS
  These results have two main implications for melanoma treatment and possibly other cancers. First, the susceptibility of ABCB5+ and JARID1B+cells to RIT in melanoma might be indicative of their susceptibility to antibody-targeted radiation in other cancers where they are present as well. Second, specifically targeting cancer stem cells with radiolabeled antibodies to ABCB5 or JARID1B might help to completely eradicate cancer stem cells in various cancers.
authors.affiliation: Department of Radiology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Thomas
authors.initials: T
authors.lastname: Jandl
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Revskaya
authors.forename: Zewei
authors.initials: Z
authors.lastname: Jiang
authors.forename: Matthew
authors.initials: M
authors.lastname: Harris
authors.forename: Olena
authors.initials: O
authors.lastname: Dorokhova
authors.forename: Dina
authors.initials: D
authors.lastname: Tsukrov
authors.forename: Arturo
authors.initials: A
authors.lastname: Casadevall
authors.forename: Ekaterina
authors.initials: E
authors.lastname: Dadachova
mesh_terms: D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1 / Q000378:metabolism; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use; D016923:Cell Death / Q000528:radiation effects; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000528:radiation effects; D005260:Female; D006801:Humans; D056484:Jumonji Domain-Containing Histone Demethylases / Q000378:metabolism; D008543:Melanins / Q000276:immunology; D008546:Melanoma, Experimental / Q000378:metabolism / Q000473:pathology* / Q000532:radiotherapy*; D051379:Mice; D014411:Neoplastic Stem Cells / Q000473:pathology* / Q000528:radiation effects*; D009687:Nuclear Proteins / Q000378:metabolism; D016499:Radioimmunotherapy; D012097:Repressor Proteins / Q000378:metabolism
chemical_list: C480744:ABCB5 protein, human; D018435:ATP Binding Cassette Transporter, Subfamily B; D020168:ATP Binding Cassette Transporter, Subfamily B, Member 1; D000911:Antibodies, Monoclonal; D008543:Melanins; D009687:Nuclear Proteins; D012097:Repressor Proteins; D056484:Jumonji Domain-Containing Histone Demethylases; C119611:KDM5B protein, human