title: Mesothelin Expression in Advanced Gastroesophageal Cancer Represents a Novel Target for Immunotherapy.
abstract: The identification of new therapeutic targets is of profound importance if we are to improve outcomes in gastroesophageal cancer. This study assessed the rate of mesothelin expression in tumors of western patients with upper gastrointestinal tract carcinomas. In addition, the AGS gastric cancer cell line was tested for sensitivity to SS1(dsFv)PE38, a mesothelin-targeting immunotoxin. Previously constructed tissue microarrays containing samples from 127 patients with gastroesophageal adenocarcinomas were examined by immunohistochemistry (IHC) for mesothelin expression. Labeling for HER2-neu, E-cadherin, and c-met were also assessed. Tumors were considered positive for mesothelin if at least moderate cytoplasmic/membranous or luminal staining was present in minimum 10% of the neoplastic cells. The AGS gastric cancer cell line was assessed for surface mesothelin expression by flow cytometry and the viability of cells treated with SS1P was measured. Gastroesophageal cancers were mesothelin positive in 64 of 127 tumors [50.4%; 95% confidence interval (CI), 41.4%-59.4%], whereas only 9 carcinomas (7.1%; 95% CI, 3.3%-13.0%) were HER2-neu IHC 3+ positive and 8 (6.6%; 95% CI, 2.9%-12.5%) were c-met positive. Mesothelin expression increased from stage I to stage IV tumors (37.5% to 56.3%, respectively, P=0.10). The AGS gastric cancer cell line was sensitive to the immunotoxin with an EC50 value in the low picomolar range (0.4 ng/mL). A gastric cancer cell line derived from a western patient was exquisitely sensitive to the mesothelin-targeted immunotoxin SS1P. Clinical trials involving novel mesothelin targeted immunotherapeutics in gastroesophageal cancer are currently in development.
authors.affiliation: *Department of Pathology ‡The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore †Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Peter B
authors.initials: PB
authors.lastname: Illei
authors.forename: Christine
authors.initials: C
authors.lastname: Alewine
authors.forename: Marianna
authors.initials: M
authors.lastname: Zahurak
authors.forename: Morgan L
authors.initials: ML
authors.lastname: Cowan
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Montgomery
authors.forename: Raffit
authors.initials: R
authors.lastname: Hassan
authors.forename: Laiman
authors.initials: L
authors.lastname: Xiang
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
authors.forename: Ronan J
authors.initials: RJ
authors.lastname: Kelly
mesh_terms: D000328:Adult; D000368:Aged; D045744:Cell Line, Tumor; D004938:Esophageal Neoplasms / Q000378:metabolism* / Q000628:therapy*; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism*; D006801:Humans; D007167:Immunotherapy; D008297:Male; D000090204:Mesothelin; D008875:Middle Aged; D013274:Stomach Neoplasms / Q000378:metabolism* / Q000628:therapy*; D055815:Young Adult
chemical_list: D058851:GPI-Linked Proteins; D000090204:Mesothelin