Combined Antitumor Activity of Oncolytic HSV-1 and EGFR/Ras/Rac1 Inhibition In Models of Malignant Peripheral Nerve Sheath Tumor
Version: Feb. 8, 2017, 6:34 p.m.

Authors:
  • Margaret H. Collins,
  • Dr. Timothy Cripe,
  • Timothy M. Crombleholme,
  • David W. Eaves,
  • Adrienne M. Hammill,
  • Mi-Ok Kim,
  • Chunyan Liu,
  • Arturo R. Maldonado,
  • Nancy Ratner,
  • Jon P. Williams,
  • Yonatan Y. Mahller,
  • Yi Zheng

There is currently no effective therapy for malignant peripheral nerve sheath tumors (MPNSTs). We previously documented that growth of human MPNST xenografts is inhibited by the epidermal growth factor receptor (EGFR) inhibitor, erlotinib, and oncolytic Herpes Simplex Viruses (oHSVs). Because a major downstream mediator of EGFR signaling is the small GTPase protein Rac, we sought to determine if MPNST cells and xenografts are affected by NSC23766, a reversible inhibitor of Rac signaling. Further, we assessed the combinatorial efficacy of NSC23766, erlotinib and oHSV. Growth of MPNST cells was inhibited by NSC23766 via induction of apoptosis and reduced proliferation. These effects were potentiated by combination with erlotinib. The combined effect of NSC23766 and erlotinib on cell growth was synergistic. Mice bearing MPNST xenografts treated with erlotinib or NSC23766 alone showed modest inhibition of tumor growth while those treated with the oHSV rRp450 showed robust reduction in tumor growth. While each targeted drug was mildly effective, tumor bearing mice that received combinations of these agents showed increased inhibition of tumor growth. Overall, NSC23766, erlotinib and rRp450 are promising antitumor agents. These data illustrate the potential utility of combinatorial therapy and provide support for translation to the clinic.

Manuscript Maintainer

Li Guo

Authors

  • Collins, Margaret H.
  • Dr. Timothy Cripe
  • Crombleholme, Timothy M.
  • Eaves, David W.
  • Hammill, Adrienne M.
  • Kim, Mi-Ok
  • Liu, Chunyan
  • Maldonado, Arturo R.
  • Ratner, Nancy
  • Williams, Jon P.
  • Yonatan Y. Mahller
  • Zheng, Yi

Version History

  • Feb. 8, 2017, 6:34 p.m. - Combined Antitumor Activity of Oncolytic HSV-1 and EGFR/Ras/Rac1 Inhibition In Models of Malignant Peripheral Nerve Sheath Tumor
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