file.pdf (2.63 MB)
0/0

Antitumor effects of EGFR antisense guanidine-based peptide nucleic acids in cancer models.

Download (2.63 MB)
journal contribution
posted on 15.02.2013 by Sufi M. Thomas, Bichismita Sahu, Srinivas Rapireddy, Raman Bahal, Sarah E. Wheeler, Eva M. Procopio, Joseph Kim, Sonali C. Joyce, Sarah Contrucci, Yun Wang, Simion I. Chiosea, Kira L. Lathrop, Simon Watkins, Jennifer R. Grandis, Bruce Armitage

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.

History

Publisher Statement

This document is the unedited Author’s version of a Submitted Work that was subsequently accepted for publication in ACS Chemical Biology, copyright ©2013 American Chemical Society after peer review. To access the final edited and published work see: dx.doi.org/10.1021/cb3003946

Date

15/02/2013

Exports