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

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 (yPNA)-based genomic DNA -targeted platform to silence oncogenes in vivo. yPNAs efficiently invade the mixed sequences of genomic DNA with high affinity and specificity. As a proof of concept, we establish that yPNA 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 yPNA 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.