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Poster display

4322 - Suppression of oncogene transcription - PNA as targeted cancer therapy for BRAF-V600E mutant melanoma


10 Oct 2016


Poster display


Jeffrey Rothman


Annals of Oncology (2016) 27 (6): 114-135. 10.1093/annonc/mdw368


J.H. Rothman, O. Surriga, G. Ambrosini, S. Vasudeva, G.K. Schwartz

Author affiliations

  • Molecular Pharmacology And Chemistry, Memorial Sloan-Kettering Cancer Center, 10065 - New York/US


Abstract 4322


Our aim is to target tumor cells specifically by directly suppressing their oncogenes with peptide nucleic acid (PNA) oligonucleotide analogues. These bind to DNA over 1000-fold more avidly than its native complement and when conjugated to delivery peptides can be made nuclear and cell membrane permeable. We have employed these PNA oligomers to target BRAF V600E in a sequence-specific complementary manner in order to disrupt transcription.


For these studies, we have employed a novel delivery peptide conjugated to PNA modified to increase both cellular delivery and stability towards its target. We have assessed its ability to obstruct BRAF V600E transcription specifically in variety of cell lines by monitoring suppression of cell proliferation, BRAF V600E protein expression, and mRNA transcription. Tumor reduction was assessed through xenograft mouse models.


Our results indicate that exposure of the melanoma cell lines to a modified PNA-peptide conjugate selective for BRAF V600E results in a concentration-dependent inhibition of cell growth that is specific for the BRAF V600E mutant melanoma cell lines with an IC50 range of 250 to 500 nM. Moreover, there is no inhibition of BRAF WT cell growth at these concentrations. This is associated with suppression of BRAF V600E protein over time. Furthermore, BRAF V600E protein expression was suppressed for up to 6 days following initial exposure proving its durability of inhibition. Exposure to this modified PNA-peptide down-regulates BRAF V600E mRNA transcription exclusively in the mutant cell lines. Live cell imaging of BRAF V600E mutant cells indicates localization of fluorescein-labeled PNA-delivery peptide conjugates to the nucleus within 3 hours of treatment. Xenograft mouse studies show reversal of tumor burden after four doses continuing for days following the last dose with a maximum tolerated dose to at least 50mg/kg.


Our results indicate that these PNA-peptide derivatives could represent a novel and promising new therapy for patients with BRAF V600E mutant melanoma, and this technology could be applied to a multitude of other cancers either with specific translocations or mutations differing from wild-type cells even by only a single base pair.

Clinical trial identification


Legal entity responsible for the study

Memorial Sloan Kettering Cancer Center


Memorial Sloan Kettering Cancer Center


All authors have declared no conflicts of interest.

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