Journal of Neuro-Oncology

, Volume 135, Issue 1, pp 47–56 | Cite as

The efficacy of lapatinib and nilotinib in combination with radiation therapy in a model of NF2 associated peripheral schwannoma

  • Iddo Paldor
  • Sara Abbadi
  • Nicolas Bonne
  • Xiaobu Ye
  • Fausto J. Rodriguez
  • David Rowshanshad
  • MariaLisa Itzoe
  • Veronica Vigilar
  • Marco Giovannini
  • Henry Brem
  • Jaishri O. Blakeley
  • Betty M. Tyler
Laboratory Investigation

Abstract

Neurofibromatosis type 2 (NF2), a neurogenetic condition manifest by peripheral nerve sheath tumors (PNST) throughout the neuroaxis for which there are no approved therapies. In vitro and in vivo studies presented here examine agents targeting signaling pathways, angiogenesis, and DNA repair mechanisms. In vitro dose response assays demonstrated potent activity of lapatinib and nilotinib against the mouse schwannoma SC4 (Nf2 −/−) cell line. We then examined the efficacy of everolimus, nilotinib, lapatinib, bevacizumab and radiation (RT) as mono- and combination therapies in flank and sciatic nerve in vivo NF2-PNST models. Data were analyzed using generalized linear models, two sample T-tests and paired T-tests, and linear regression models. SC4(Nf2 −/−) cells implanted in the flank or sciatic nerve showed similar rates of growth (p = 0.9748). Lapatinib, nilotinib and RT significantly reduced tumor growth rate versus controls in the in vivo flank model (p = 0.0025, 0.0062, and 0.009, respectively) whereas bevacizumab and everolimus did not. The best performers were tested in the in vivo sciatic nerve model of NF2 associated PNST, where chemoradiation outperformed nilotinib or lapatinib as single agents (nilotinib vs. nilotinib + RT, p = 0.0001; lapatinib versus lapatinib + RT, p < 0.0001) with no observed toxicity. There was no re-growth of tumors even 14 days after treatment was stopped. The combination of either lapatinib or nilotinib with RT resulted in greater delays in tumor growth rate than any modality alone. This data suggest that concurrent low dose RT and targeted therapy may have a role in addressing progressive PNST in patients with NF2.

Keywords

Lapatinib Nilotinib Radiation Peripheral schwannoma 

Notes

Acknowledgements

We thank Mr. and Mrs. Peter Jennison for their kind and generous support. We would also like to thank Eden Paldor for her technical assistance.

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Copyright information

© Springer Science+Business Media, LLC 2017

Authors and Affiliations

  • Iddo Paldor
    • 1
  • Sara Abbadi
    • 1
  • Nicolas Bonne
    • 7
  • Xiaobu Ye
    • 1
  • Fausto J. Rodriguez
    • 3
    • 6
  • David Rowshanshad
    • 1
  • MariaLisa Itzoe
    • 1
  • Veronica Vigilar
    • 1
  • Marco Giovannini
    • 8
  • Henry Brem
    • 1
    • 3
    • 4
    • 5
  • Jaishri O. Blakeley
    • 1
    • 2
    • 3
  • Betty M. Tyler
    • 1
  1. 1.Departments of NeurosurgeryJohns Hopkins University School of MedicineBaltimoreUSA
  2. 2.Departments of NeurologyJohns Hopkins University School of MedicineBaltimoreUSA
  3. 3.Departments of OncologyJohns Hopkins University School of MedicineBaltimoreUSA
  4. 4.Departments of OphthalmologyJohns Hopkins University School of MedicineBaltimoreUSA
  5. 5.Departments of Biomedical EngineeringJohns Hopkins University School of MedicineBaltimoreUSA
  6. 6.Departments of PathologyJohns Hopkins University School of MedicineBaltimoreUSA
  7. 7.Department of Otology and NeurotologyUniversity Hospital of Lille, and INSERM U1008, University of LilleLilleFrance
  8. 8.Department of Head and Neck SurgeryDavid Geffen School of Medicine at UCLALos AngelesUSA

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