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Mutant KRAS is a druggable target for pancreatic cancer

Elina Zorde Khvalevsky1, Racheli Gabai, Itzhak Haim Rachmut

  • 1Silenseed LTD, and Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Medical Center, Jerusalem 91120, Israel.

Proceedings of the National Academy of Sciences of the United States of America
|December 4, 2013
PubMed

Insights

This study presents a novel siRNA delivery system (LODER) that effectively targets mutated KRAS in pancreatic cancer. The siG12D LODER platform demonstrates prolonged stability and therapeutic efficacy, making KRAS a druggable target.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biomedical Engineering

Background:

  • Pancreatic ductal adenocarcinoma (PDA) is a challenging cancer with limited treatment options.
  • The mutated KRAS oncogene is a key driver of PDA but has been considered undruggable.

Purpose of the Study:

  • To develop and evaluate a novel RNA interference-based approach targeting mutated KRAS in PDA.
  • To assess the efficacy of a prolonged siRNA delivery system (LODER) for pancreatic cancer therapy.

Main Methods:

  • Development of a Local Drug EluteR (LODER) system for sustained siRNA release (siG12D LODER).
  • In vitro and in vivo evaluation of siG12D LODER's structural, release, and delivery properties.
  • Assessment of anti-tumor effects in subcutaneous and orthotopic mouse models, including KRAS signaling pathway analysis.

Main Results:

  • The siG12D LODER system demonstrated stability and activity in vivo for up to 155 days.
  • Treatment with siG12D LODER significantly reduced KRAS levels, inhibited PDA cell proliferation and epithelial-mesenchymal transition.
  • In vivo, siG12D LODER impeded tumor growth and prolonged survival in mouse models.

Conclusions:

  • The developed LODER platform offers a safe, reproducible, and effective method for prolonged local siRNA delivery.
  • This technology protects siRNA from degradation and demonstrates that mutated KRAS can be targeted therapeutically in PDA.
Keywords:
gene therapytargeted therapy

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