Antitumor efficacy of a sequence-specific DNA-targeted γPNA-based c-Myc inhibitor

Cell Rep Med. 2024 Jan 16;5(1):101354. doi: 10.1016/j.xcrm.2023.101354. Epub 2024 Jan 5.

Abstract

Targeting oncogenes at the genomic DNA level can open new avenues for precision medicine. Significant efforts are ongoing to target oncogenes using RNA-targeted and protein-targeted platforms, but no progress has been made to target genomic DNA for cancer therapy. Here, we introduce a gamma peptide nucleic acid (γPNA)-based genomic DNA-targeted platform to silence oncogenes in vivo. γPNAs efficiently invade the mixed sequences of genomic DNA with high affinity and specificity. As a proof of concept, we establish that γPNA can inhibit c-Myc transcription in multiple cell lines. We evaluate the in vivo efficacy and safety of genomic DNA targeting in three pre-clinical models. We also establish that anti-transcription γPNA in combination with histone deacetylase inhibitors and chemotherapeutic drugs results in robust antitumor activity in cell-line- and patient-derived xenografts. Overall, this strategy offers a unique therapeutic platform to target genomic DNA to inhibit oncogenes for cancer therapy.

Keywords: HDACi; PNA; c-Myc; cancer therapy; chemotherapy; histone deacetylase inhibitors; lymphoma; nuclear delivery; peptide nucleic acid; transcription inhibition.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • DNA / genetics
  • Humans
  • Neoplasms* / drug therapy
  • Neoplasms* / genetics
  • Nucleic Acids*
  • Peptide Nucleic Acids* / genetics
  • Peptide Nucleic Acids* / pharmacology
  • RNA

Substances

  • Nucleic Acids
  • DNA
  • Peptide Nucleic Acids
  • RNA