title: Targeting a Cancer-Specific Epitope of the Epidermal Growth Factor Receptor in Triple-Negative Breast Cancer.
abstract: Triple-negative breast cancers (TNBCs) are typically more aggressive and result in poorer outcomes than other breast cancers because treatment options are limited due to lack of hormone receptors or amplified human epidermal growth factor receptor 2 (HER2). Many TNBCs overexpress the epidermal growth factor receptor (EGFR) or manifest amplification of theEGFRgene, supporting EGFR as a therapeutic target. While EGFR-directed small molecule inhibitors have shown limited effectiveness in clinical settings, use of EGFR as a mechanism of delivering enzymatic cytotoxins to TNBC has not been demonstrated.
  
  
  
  Using the single-chain variable fragment (scFv) of the 806 antibody that binds only cells with overexpressed, misfolded, or mutant variants of the EGFR, a recombinant immunotoxin was engineered through gene fusion withPseudomonas aeruginosaExotoxin A (806-PE38). The potency of 806-PE38 on reducing TNBC cell growth in vitro and in xenograft models (n ≥ 6) was examined for six TNBC cell lines. All statistical tests were two-sided.
  
  
  
  806-PE38 statistically significantly reduced the viability of all tested TNBC lines, with IC50values below 10 ng/mL for three of six cell lines, while not affecting cells with wild-type EGFR (IC50>300 ng/mL). Systemic treatments with 806-PE38 vs vehicle resulted in statistically significantly reduced tumor burdens (806-PE38 mean = 128 mm(3)[SD = 46 mm(3)] vs vehicle mean = 749 mm(3)[SD = 395 mm(3)], P = .001) and increased median survival (806-PE38 median = 82 days vs vehicle median = 50 days,P= .01) in a MDA-MB-468 TNBC mouse xenograft. Deletion of the catalytic residue eliminated both cytotoxic activity in vitro and the reduction in tumor burden and survival (P= .52).
  
  
  
  These data support the further development of the 806-PE38 immunotoxin as a therapeutic agent for the treatment of patients with EGFR-positive TNBC. Follow-up experiments with combination therapies will be attempted to achieve full remissions.
authors.affiliation: Affiliations of authors: Biotherapy Section, Laboratory of Molecular Biology (NS, AA, RS, DF), and Experimental Pathology Laboratory, Laboratory of Pathology (SMH), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Nathan
authors.initials: N
authors.lastname: Simon
authors.affiliation: Affiliations of authors: Biotherapy Section, Laboratory of Molecular Biology (NS, AA, RS, DF), and Experimental Pathology Laboratory, Laboratory of Pathology (SMH), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Antonella
authors.initials: A
authors.lastname: Antignani
authors.affiliation: Affiliations of authors: Biotherapy Section, Laboratory of Molecular Biology (NS, AA, RS, DF), and Experimental Pathology Laboratory, Laboratory of Pathology (SMH), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Robert
authors.initials: R
authors.lastname: Sarnovsky
authors.affiliation: Affiliations of authors: Biotherapy Section, Laboratory of Molecular Biology (NS, AA, RS, DF), and Experimental Pathology Laboratory, Laboratory of Pathology (SMH), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: Stephen M
authors.initials: SM
authors.lastname: Hewitt
authors.affiliation: Affiliations of authors: Biotherapy Section, Laboratory of Molecular Biology (NS, AA, RS, DF), and Experimental Pathology Laboratory, Laboratory of Pathology (SMH), Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD.
authors.forename: David
authors.initials: D
authors.lastname: FitzGerald
mesh_terms: D036002:ADP Ribose Transferases / Q000494:pharmacology / Q000627:therapeutic use*; D000818:Animals; D001427:Bacterial Toxins / Q000494:pharmacology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004337:Drug Carriers; D000939:Epitopes / Q000276:immunology; D066246:ErbB Receptors / Q000235:genetics / Q000276:immunology*; D005098:Exotoxins / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology / Q000627:therapeutic use*; D000922:Immunotoxins / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D058990:Molecular Targeted Therapy; D009368:Neoplasm Transplantation; D011994:Recombinant Proteins / Q000627:therapeutic use; D015996:Survival Rate; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000276:immunology* / Q000473:pathology; D047368:Tumor Burden / Q000187:drug effects; D037521:Virulence Factors / Q000494:pharmacology / Q000627:therapeutic use*; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D004337:Drug Carriers; D000939:Epitopes; D066246:ErbB Receptors; D005098:Exotoxins; D007155:Immunologic Factors; D000922:Immunotoxins; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A