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Development of immunohistochemistry assays to assess GALNT14 and FUT3/6 in clinical trials of dulanermin and drozitumab.

AbstractPURPOSE:
In vitro sensitivity to the proapoptotic receptor agonists dulanermin (rhApo2L/TRAIL) and drozitumab (DR5-agonist antibody) is strongly predicted by the expression of the O-glycosylation enzymes GALNT14 in non-small cell lung cancer (NSCLC) cell lines (among others) and of FUT3/6 in colorectal cancer (CRC) cell lines. We developed immunohistochemistry (IHC) assays that measure GALNT14 and FUT3/6 levels in archival formalin-fixed, paraffin-embedded human tumor tissue to determine marker prevalence in NSCLC and CRC tissue and to enable the future examination of these markers in clinical trials.
EXPERIMENTAL DESIGN:
GALNT14 or FUT3/6 ELISA-positive hybridoma clones were screened through IHC on cell pellets with known mRNA levels. The specificity of staining was examined in cell lines, normal tissue, and tumor tissue.
RESULTS:
GALNT14 and FUT3/6 IHC exhibited a golgi staining pattern and correlated with GALNT14 and FUT3/6 (but not GALNT2 and FUT4) mRNA expression levels in cell lines and normal tissues, suggesting specificity. GALNT14 and FUT3/6 H-scores were significantly higher in cell lines sensitive to dulanermin (P = 0.01 and P = 0.0004, respectively) and drozitumab (P = 0.03 and P < 0.0001, respectively) versus resistant cell lines. GALNT14 and FUT3/6 H-scores varied widely, with approximately 45% of NSCLC samples exhibiting weak to moderate GALNT14 staining (H-score of at least 25) and 70% of CRC samples exhibiting moderate to strong FUT3/6 staining (H-score of at least 125).
CONCLUSIONS:
GALNT14 and FUT3/6 expression can be assessed in human tumors using sensitive and specific IHC assays. Both assays are being deployed in ongoing clinical trials of dulanermin and drozitumab to assess potential utility for patient selection.
AuthorsHoward M Stern, Mary Padilla, Klaus Wagner, Lukas Amler, Avi Ashkenazi
JournalClinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 5 Pg. 1587-96 (Mar 01 2010) ISSN: 1557-3265 [Electronic] United States
PMID20179215 (Publication Type: Journal Article, Validation Study)
Chemical References
  • Antibodies, Monoclonal
  • Antineoplastic Agents
  • Biomarkers, Tumor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human
  • Fucosyltransferases
  • N-Acetylgalactosaminyltransferases
  • 3-galactosyl-N-acetylglucosaminide 4-alpha-L-fucosyltransferase
  • FUT6 protein, human
Topics
  • Antibodies, Monoclonal (therapeutic use)
  • Antineoplastic Agents (therapeutic use)
  • Biomarkers, Tumor (analysis, biosynthesis)
  • Carcinoma, Non-Small-Cell Lung (drug therapy, metabolism)
  • Cell Line, Tumor
  • Clinical Trials as Topic
  • Colorectal Neoplasms (drug therapy, metabolism)
  • Enzyme-Linked Immunosorbent Assay
  • Fucosyltransferases (analysis, biosynthesis)
  • Humans
  • Immunohistochemistry (methods)
  • Lung Neoplasms (drug therapy, metabolism)
  • N-Acetylgalactosaminyltransferases (analysis, biosynthesis)
  • Sensitivity and Specificity
  • TNF-Related Apoptosis-Inducing Ligand (therapeutic use)

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