title: GPNMB expression in uveal melanoma: a potential for targeted therapy.
abstract: Uveal melanoma is an aggressive disease without effective adjuvant therapy for metastases. Despite genomic differences between cutaneous and uveal melanomas, therapies based on shared biological factors could be effective against both tumor types. High expression of glycoprotein-NMB (GPNMB) in cutaneous melanomas led to the development of CDX-011 (glembatumumab vedotin), a fully human monoclonal antibody against the extracellular domain of GPNMB conjugated to the cytotoxic microtubule toxin monomethylauristatin E. Ongoing phase II trials suggest that CDX-011 has activity against advanced cutaneous melanomas. To determine the potential role of CDX-011 in uveal melanomas, we studied their GPNMB expression. Paraffin-embedded tissues from 22 uveal melanomas treated by enucleation from 2004-2007 at one institution were evaluated immunohistochemically for expression of GPNMB using biotinylated CDX-011 (unconjugated) antibody. Melanoma cells were evaluated for percentage and intensity of expression. Spectral imaging was used in one case with high melanin content. Clinical data were reviewed. Twelve women and 10 men with a median age of 58.7 years (range: 28-83 years) were included. Eighteen of 21 tumors evaluated immunohistochemically (85.7%) expressed GPNMB in 10-90% of tumor cells with variable intensity (5 tumors, 1+; 11, 2+; and 2, 3+). Eleven of 18 tumors (61.1%) expressed GPNMB in >or=50% of cells. Spectral imaging showed diffuse CDX-011 (unconjugated) reactivity in the remaining case. Uveal melanoma, like cutaneous melanoma, commonly expresses GPNMB. Ongoing clinical trials of CDX-011 should be extended to patients with metastatic uveal melanoma to determine potential efficacy in this subset of patients with melanoma.
authors.affiliation: Department of Pathology, Section of Ophthalmology, The University of Texas MD Anderson Cancer Center, Houston, Texas 77030, USA. mdwillia@mdanderson.org
authors.forename: Michelle D
authors.initials: MD
authors.lastname: Williams
authors.forename: Bita
authors.initials: B
authors.lastname: Esmaeli
authors.forename: Aydin
authors.initials: A
authors.lastname: Soheili
authors.forename: Ronit
authors.initials: R
authors.lastname: Simantov
authors.forename: Dan S
authors.initials: DS
authors.lastname: Gombos
authors.forename: Agop Y
authors.initials: AY
authors.lastname: Bedikian
authors.forename: Patrick
authors.initials: P
authors.lastname: Hwu
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000911:Antibodies, Monoclonal / Q000378:metabolism / Q000494:pharmacology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D018796:Immunoconjugates; D008297:Male; D008495:Medical Oncology / Q000379:methods; D008545:Melanoma / Q000378:metabolism*; D008562:Membrane Glycoproteins / Q000096:biosynthesis*; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009842:Oligopeptides / Q000494:pharmacology; D014604:Uveal Neoplasms / Q000378:metabolism*
chemical_list: D000911:Antibodies, Monoclonal; C503042:GPNMB protein, human; D018796:Immunoconjugates; D008562:Membrane Glycoproteins; D009842:Oligopeptides; C551271:glembatumumab vedotin; C495575:monomethyl auristatin E