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Proffered Paper session - Basic Science

861 - Suppression of KRAS-G12D and BRAF-V600E Oncogene Transcription with PNA-conjugates

Date

28 Sep 2019

Session

Proffered Paper session - Basic Science

Topics

Basic Science

Tumour Site

Presenters

Jeffrey Rothman

Citation

Annals of Oncology (2019) 30 (suppl_5): v1-v24. 10.1093/annonc/mdz238

Authors

J.H. Rothman, G. Schwartz, O. Surriga, G. Ambrosini

Author affiliations

  • Hematology-oncology, Columbia University Medical Center College of Physicians & Surgeons - New York Presbyterian Hospital, 10032 - New York/US

Resources

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Abstract 861

Background

We have developed a strategy to block transcription of oncogenes such as BRAF V600E and KRAS G12D directly using modified complementary peptide nucleic acid (PNA) oligomers that target oncogenesis specifically causing inhibition of tumour growth. This proof of principle strategy against BRAF V600E and KRAS G12D in vitro and in vivo should provide a new means to develop PNA-delivery peptide conjugates as targeted drug therapeutics across a broad range of oncogenes that drive cancer cell growth.

Methods

Obstruction of KRAS G12D and BRAF V600E expression was evaluated through suppression of cell proliferation and specific mRNA transcription. Tumour reduction was assessed through Xenograft mouse models.

Results

Exposure of KRAS G12D-dependent cell line to modified PNA-peptide conjugate complementary to KRAS G12D mutation sequence also results in concentration-dependent and time-dependent inhibition of cell growth and specific and complete suppression in mRNA transcription. Cell lines expressing KRAS WT and KRAS G12C, both differing by a single nucleobase, show no suppression. Exposure of the melanoma cell lines to a modified PNA-peptide conjugate complementary to BRAF V600E mutation sequence results in a concentration-dependent and time-dependent inhibition of cell growth that is specific for the BRAF V600E mutant melanoma cell lines with inhibition of mRNA and protein expression. Xenograft mouse trials show tumour growth delay and necrosis compared to PNA controls. This 50mg/kg dose was well tolerated without associated weight loss. By H&E staining, tumor tissue from trials shows ablation and extensive scaring upon exposure to BRAF V600E-complementary PNA-peptide conjugate whereas saline and scramble PNA sequence controls do not. Similarly quantitative measurement shows a 2.5-fold decrease in Ki67 and a 3-fold increase in TUNEL expression.

Conclusions

Our results indicate that these PNA-peptide derivatives could represent a novel and promising new therapy for patients with genes specific for and causative of tumorigenesis. This strategy could be applied to a multitude of cancers either with specific translocations or mutations differing from wild-type cells even by only a single base pair.

Clinical trial identification

Editorial acknowledgement

Legal entity responsible for the study

The authors.

Funding

Celgene, Fortress Biotech.

Disclosure

All authors have declared no conflicts of interest.

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