title: Tumor response to combination celecoxib and erlotinib therapy in non-small cell lung cancer is associated with a low baseline matrix metalloproteinase-9 and a decline in serum-soluble E-cadherin.
abstract: BACKGROUND
  Cyclooxygenase-2 overexpression may mediate resistance to epidermal growth factor receptor tyrosine kinase inhibition through prostaglandin E2-dependent promotion of epithelial to mesenchymal transition (EMT). Suppression of epithelial markers, such as E-cadherin, can lead to resistance to erlotinib. Prostaglandin E2 down-regulates E-cadherin expression by up-regulating transcriptional repressors, including ZEB1 and Snail. Furthermore, E-cadherin can be modulated by matrix metalloproteinases (MMPs) and tissue inhibitors of MMPs (TIMPs), promoting tumor invasion and metastasis. Markers of EMT and tumor invasion were evaluated in patient serum from a phase I clinical trial investigating the combination of celecoxib and erlotinib in non-small cell lung cancer (NSCLC) patients.
  
  
  METHODS
  Samples from 22 subjects were evaluated. Soluble E-cadherin (sEC) was evaluated by enzyme linked immunosorbent assay in patient serum at baseline, week 4, and week 8 of treatment. Other markers of EMT and angiogenesis were evaluated by enzyme linked immunosorbent assay, including MMP-9, TIMP-1, and CCL15.
  
  
  RESULTS
  Serum sEC, MMP-9, TIMP-1, and CCL15 levels were determined at baseline and week 8. Patients with a partial response to therapy had a significant decrease in sEC, TIMP-1, and CCL15 at week 8. In patients who responded to the combination therapy, baseline MMP-9 was significantly lower compared with nonresponders (p = 0.006).
  
  
  CONCLUSIONS
  sEC, MMP-9, TIMP-1, and CCL15 levels correlate with response to combination therapy with erlotinib and celecoxib in patients with NSCLC. A randomized phase II trial is planned comparing erlotinib and celecoxib with erlotinib plus placebo in advanced NSCLC. This study will prospectively assess these and other biomarkers in serum and tumor tissue.
authors.affiliation: Department of Medical Oncology and Therapeutics Research, City of Hope and Beckman Research Institute, Duarte, California, USA. kreckamp@coh.org
authors.forename: Karen L
authors.initials: KL
authors.lastname: Reckamp
authors.forename: Brian K
authors.initials: BK
authors.lastname: Gardner
authors.forename: Robert A
authors.initials: RA
authors.lastname: Figlin
authors.forename: David
authors.initials: D
authors.lastname: Elashoff
authors.forename: Kostyantyn
authors.initials: K
authors.lastname: Krysan
authors.forename: Mariam
authors.initials: M
authors.lastname: Dohadwala
authors.forename: Jenny
authors.initials: J
authors.lastname: Mao
authors.forename: Sherven
authors.initials: S
authors.lastname: Sharma
authors.forename: Landon
authors.initials: L
authors.lastname: Inge
authors.forename: Ayyappan
authors.initials: A
authors.lastname: Rajasekaran
authors.forename: Steven M
authors.initials: SM
authors.lastname: Dubinett
mesh_terms: D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology* / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000097:blood*; D015820:Cadherins / Q000097:blood*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy*; D000068579:Celecoxib; D019742:Chemokines, CC / Q000097:blood; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D019008:Drug Resistance, Neoplasm; D066246:ErbB Receptors / Q000037:antagonists & inhibitors; D000069347:Erlotinib Hydrochloride; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy*; D019402:Macrophage Inflammatory Proteins / Q000097:blood; D020780:Matrix Metalloproteinase 9 / Q000097:blood*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D011720:Pyrazoles / Q000008:administration & dosage / Q000494:pharmacology; D011799:Quinazolines / Q000008:administration & dosage / Q000494:pharmacology; D013449:Sulfonamides / Q000008:administration & dosage / Q000494:pharmacology; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000097:blood
chemical_list: D014408:Biomarkers, Tumor; C108814:CCL15 protein, human; D015820:Cadherins; D019742:Chemokines, CC; D016861:Cyclooxygenase Inhibitors; D019402:Macrophage Inflammatory Proteins; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D011799:Quinazolines; D013449:Sulfonamides; D019715:Tissue Inhibitor of Metalloproteinase-1; D000069347:Erlotinib Hydrochloride; D066246:ErbB Receptors; D020780:Matrix Metalloproteinase 9; D000068579:Celecoxib