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.

Recent Implementations of Molecular Photoswitches into Smart Materials and Biological Systems

“…PNA oligomers efficiently hybridize to DNA and RNA through standard Watson–Crick and Hoogsteen base pairing, with high affinity and sequence specificity. Therefore, PNA oligomers found applications for in vivo nucleotide sensing, or as promising antisense agents . Short triplex‐forming PNA oligomers terminated with AB‐containing monomeric units have been used to photomodulate the transcription process of the egfp gene with T7 RNA polymerase …”

Phase 1 study of EGFR‐antisense DNA, cetuximab, and radiotherapy in head and neck cancer with preclinical correlatives

“…We previously demonstrated that EGFR-AS was as effective as cetuximab alone in reducing tumor growth in a 1483 xenograft model, whereas EGFR-sense treatment was not, indicating a sequence-specific treatment effect rather than a nonspecific effect of plasmid treatment. 16 After establishing that dual EGFR targeting with cetuximab and EGFR-AS reduced HNSCC cell line viability, we evaluated the combination in a 4-arm in vivo experiment. Two groups of 10 mice were inoculated in the flank bilaterally with 1483 cells, then randomized to intraperitoneal vehicle versus cetuximab.…”

The role of the PI3K/Akt/mTOR signalling pathway in human cancers induced by infection with human papillomaviruses

“…HPV infection accompanied by E6/E7 expression activates this signalling pathway by altering multiple cellular and molecular events to drive carcinogenesis [ 16 - 18 ]. The PI3K pathway is unique, in that all of the major components of this pathway have been found to be frequently amplified or mutated in HPV-induced cancers [ 19 - 24 ]. The PI3K/Akt/mTOR signalling pathway mediates the multiple cellular and molecular functions through the altered expression of its targeted genes, which are critical to tumor initiation, progression and outcomes [ 25 , 26 ].…”