title: Antitumor effects of EGFR antisense guanidine-based peptide nucleic acids in cancer models.
abstract: Peptide nucleic acids have emerged over the past two decades as a promising class of nucleic acid mimics because of their strong binding affinity and sequence selectivity toward DNA and RNA, and resistance to enzymatic degradation by proteases and nucleases. While they have been shown to be effective in regulation of gene expression in vitro, and to a small extent in vivo, their full potential for molecular therapy has not yet been fully realized due to poor cellular uptake. Herein, we report the development of cell-permeable, guanidine-based peptide nucleic acids targeting the epidermal growth factor receptor (EGFR) in preclinical models as therapeutic modality for head and neck squamous cell carcinoma (HNSCC) and nonsmall cell lung cancer (NSCLC). A GPNA oligomer, 16 nucleotides in length, designed to bind to EGFR gene transcript elicited potent antisense effects in HNSCC and NSCLC cells in preclinical models. When administered intraperitoneally in mice, EGFRAS-GPNA was taken-up by several tissues including the xenograft tumor. Systemic administration of EGFRAS-GPNA induced antitumor effects in HNSCC xenografts, with similar efficacies as the FDA-approved EGFR inhibitors: cetuximab and erlotinib. In addition to targeting wild-type EGFR, EGFRAS-GPNA is effective against the constitutively active EGFR vIII mutant implicated in cetuximab resistance. Our data reveals that GPNA is just as effective as a molecular platform for treating cetuximab resistant cells, demonstrating its utility in the treatment of cancer.
authors.affiliation: Department of Otolaryngology, University of Pittsburgh and University of Pittsburgh Cancer Institute, 200 Lothrop Street, Pittsburgh, Pennsylvania 15213, USA. smt30@pitt.edu
authors.forename: Sufi M
authors.initials: SM
authors.lastname: Thomas
authors.forename: Bichismita
authors.initials: B
authors.lastname: Sahu
authors.forename: Srinivas
authors.initials: S
authors.lastname: Rapireddy
authors.forename: Raman
authors.initials: R
authors.lastname: Bahal
authors.forename: Sarah E
authors.initials: SE
authors.lastname: Wheeler
authors.forename: Eva M
authors.initials: EM
authors.lastname: Procopio
authors.forename: Joseph
authors.initials: J
authors.lastname: Kim
authors.forename: Sonali C
authors.initials: SC
authors.lastname: Joyce
authors.forename: Sarah
authors.initials: S
authors.lastname: Contrucci
authors.forename: Yun
authors.initials: Y
authors.lastname: Wang
authors.forename: Simion I
authors.initials: SI
authors.lastname: Chiosea
authors.forename: Kira L
authors.initials: KL
authors.lastname: Lathrop
authors.forename: Simon
authors.initials: S
authors.lastname: Watkins
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.forename: Bruce A
authors.initials: BA
authors.lastname: Armitage
authors.forename: Danith H
authors.initials: DH
authors.lastname: Ly
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology*; D002289:Carcinoma, Non-Small-Cell Lung / Q000188:drug therapy / Q000473:pathology; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004354:Drug Screening Assays, Antitumor; D066246:ErbB Receptors / Q000235:genetics* / Q000378:metabolism; D019791:Guanidine / Q000737:chemistry / Q000494:pharmacology*; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000473:pathology; D006801:Humans; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D051379:Mice; D016376:Oligonucleotides, Antisense / Q000737:chemistry / Q000494:pharmacology*; D020135:Peptide Nucleic Acids / Q000737:chemistry / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D013329:Structure-Activity Relationship
chemical_list: D000970:Antineoplastic Agents; D016376:Oligonucleotides, Antisense; D020135:Peptide Nucleic Acids; D066246:ErbB Receptors; D019791:Guanidine