title: Targeting Glycoprotein NMB With Antibody-Drug Conjugate, Glembatumumab Vedotin, for the Treatment of Osteosarcoma.
abstract: BACKGROUND
  Cure rates for children and young adults with osteosarcoma have remained stagnant over the past three decades. Targeting glycoprotein non-metastatic b (GPNMB) with the antibody-drug conjugate glembatumumab vedotin has improved outcomes for patients with melanoma and breast cancer. The potential utility of targeting GPNMB in osteosarcoma was explored.
  
  
  METHODS
  GPNMB protein expression was evaluated by immunohistochemistry in human osteosarcoma tumor samples and by enzyme-linked immunosorbent assay (ELISA) in osteosarcoma cell lines. mRNA expression was measured by quantitative PCR in primary osteosarcoma samples and cell lines. Surface GPNMB expression was evaluated by flow cytometry and correlated with in vitro and in vivo cytotoxicity of glembatumumab vedotin.
  
  
  RESULTS
  Sixty seven human osteosarcoma samples were evaluated by immunohistochemistry, including 12 samples from initial biopsy, 38 samples from definitive surgery, and 17 from the time of disease recurrence. GPNMB was expressed in 92.5% (62/67) of osteosarcoma samples. All primary osteosarcoma samples expressed high levels of GPNMB mRNA. Glembatumumab induced cytotoxic effects in 74% (14/19) of osteosarcoma cell lines, and GPNMB protein levels correlated with glembatumumab in vitro cytotoxicity (r = -0.46, P = 0.04). All osteosarcoma cell lines demonstrated surface GPNMB expression.
  
  
  CONCLUSIONS
  GPNMB is expressed in osteosarcoma and targeting GPNMB with the antibody-drug conjugate glembatumumab vedotin demonstrates osteosarcoma cytotoxic activity. Clinical trials are indicated to assess the efficacy of targeting GPNMB in patients with osteosarcoma.
authors: Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors: Michael
authors: M
authors: Roth
authors: Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors: David M
authors: DM
authors: Barris
authors: Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors: Sajida
authors: S
authors: Piperdi
authors: Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors: Vicky
authors: V
authors: Kuo
authors: Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors: Stephanie
authors: S
authors: Everts
authors: Department of Orthopaedic Surgery, Montefiore Medical Center and the Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors: David
authors: D
authors: Geller
authors: Greehey Children's Cancer Research Institute, University of Texas Health Science Center, San Antonio, Texas.
authors: Peter
authors: P
authors: Houghton
authors: Division of Pediatric Hematology/Oncology, A.I. duPont Hospital for Children, Wilmington, Delaware.
authors: E Anders
authors: EA
authors: Kolb
authors: Celldex Therapeutics, Branford, Connecticut.
authors: Thomas
authors: T
authors: Hawthorne
authors: Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.
authors: Jonathan
authors: J
authors: Gill
authors: Division of Pediatric Hematology/Oncology, Children's Hospital at Montefiore, Albert Einstein College of Medicine, Bronx, New York.|Department of Pediatrics and Molecular Pharmacology, Albert Einstein College of Medicine, Bronx, New York.
authors: Richard
authors: R
authors: Gorlick
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D001859:Bone Neoplasms / Q000188:drug therapy*; D002460:Cell Line; D002648:Child; D002675:Child, Preschool; D003601:Cytotoxicity Tests, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D005434:Flow Cytometry; D015870:Gene Expression; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use*; D007150:Immunohistochemistry; D008562:Membrane Glycoproteins / Q000032:analysis / Q000187:drug effects* / Q000235:genetics; D008875:Middle Aged; D012516:Osteosarcoma / Q000188:drug therapy*; D012333:RNA, Messenger / Q000032:analysis; D060888:Real-Time Polymerase Chain Reaction; D046888:Tissue Array Analysis
chemical_list: D000911:Antibodies, Monoclonal; C503042:GPNMB protein, human; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D012333:RNA, Messenger; C551271:glembatumumab vedotin
keywords: GPNMB; antibody-drug conjugate; glembatumumab vedotin; osteosarcoma