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


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.


Lapatinib Nilotinib Radiation Peripheral schwannoma 



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.


  1. 1.
    Lloyd SK, Evans DG (2013) Neurofibromatosis type 2 (NF2): diagnosis and management. Handb Clin Neurol 115:957–967CrossRefPubMedGoogle Scholar
  2. 2.
    Evans DG (2009) Neurofibromatosis type 2 (NF2): a clinical and molecular review. Orphanet J Rare Dis 4:16CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Stamenkovic I, Yu Q (2010) Merlin, a “magic” linker between extracellular cues and intracellular signaling pathways that regulate cell motility, proliferation, and survival. Current Protein Pept Sci 11(6):471–484CrossRefGoogle Scholar
  4. 4.
    Lee JY, Kim H, Ryu CH et al (2004) Merlin, a tumor suppressor, interacts with transactivation-responsive RNA-binding protein and inhibits its oncogenic activity. J Biol Chem 279(29):30265–30273CrossRefPubMedGoogle Scholar
  5. 5.
    Hamaratoglu F, Willecke M, Kango-Singh M et al (2006) The tumour-suppressor genes NF2/Merlin and Expanded act through Hippo signalling to regulate cell proliferation and apoptosis. Nat Cell Biol 8(1):27–36CrossRefPubMedGoogle Scholar
  6. 6.
    Wong HK, Shimizu A, Kirkpatrick ND et al (2012) Merlin/NF2 regulates angiogenesis in schwannomas through a Rac1/semaphorin 3F-dependent mechanism. Neoplasia 14(2):84–94CrossRefPubMedPubMedCentralGoogle Scholar
  7. 7.
    Plotkin SR, Merker VL, Muzikansky A, Barker FG 2nd, Slattery W 3rd (2014) Natural history of vestibular schwannoma growth and hearing decline in newly diagnosed neurofibromatosis type 2 patients. Otol Neurotol 35(1):e50–e56CrossRefPubMedGoogle Scholar
  8. 8.
    Paldor I, Chen AS, Kaye AH (2016) Growth rate of vestibular schwannoma. J Clin Neurosci 32:1–8. doi: 10.1016/j.jocn.2016.05.003 CrossRefPubMedGoogle Scholar
  9. 9.
    Elsharkawy M, Xu Z, Schlesinger D, Sheehan JP (2012) Gamma Knife surgery for nonvestibular schwannomas: radiological and clinical outcomes. J Neurosurg 116(1):66–72CrossRefPubMedGoogle Scholar
  10. 10.
    Blakeley JO, Ye X, Duda DG et al (2016) Efficacy and biomarker study of bevacizumab for hearing loss resulting from neurofibromatosis type 2-associated vestibular schwannomas. J Clin Oncol 34(14):1669–1675CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Voss MH, Molina AM, Motzer RJ (2011) mTOR inhibitors in advanced renal cell carcinoma. Hematol/Oncol Clin North Am 25(4):835–852CrossRefGoogle Scholar
  12. 12.
    Fonseca PJ, Uriol E, Galvan JA et al (2013) Prolonged clinical benefit of everolimus therapy in the management of high-grade pancreatic neuroendocrine carcinoma. Case Rep Oncol 6(2):441–449CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Villarreal-Garza C, Cortes J, Andre F, Verma S (2012) mTOR inhibitors in the management of hormone receptor-positive breast cancer: the latest evidence and future directions. Ann Oncol 23(10):2526–2535CrossRefPubMedGoogle Scholar
  14. 14.
    Johansson G, Mahller YY, Collins MH et al (2008) Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors. Mol Cancer Ther 7(5):1237–1245CrossRefPubMedPubMedCentralGoogle Scholar
  15. 15.
    Giovannini M, Bonne NX, Vitte J et al (2014) mTORC1 inhibition delays growth of neurofibromatosis type 2 schwannoma. Neuro Oncol 16(4):493–504CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Karajannis MA, Legault G, Hagiwara M et al (2014) Phase II study of everolimus in children and adults with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol 16(2):292–297CrossRefPubMedGoogle Scholar
  17. 17.
    Goutagny S, Raymond E, Esposito-Farese M et al (2015) Phase II study of mTORC1 inhibition by everolimus in neurofibromatosis type 2 patients with growing vestibular schwannomas. J Neurooncol 122(2):313–320CrossRefPubMedGoogle Scholar
  18. 18.
    Guarneri V, Generali DG, Frassoldati A et al (2014) Double-blind, placebo-controlled, multicenter, randomized, phase IIb neoadjuvant study of letrozole-lapatinib in postmenopausal hormone receptor-positive, human epidermal growth factor receptor 2-negative, operable breast cancer. J Clin Oncol 32(10):1050–1057CrossRefPubMedGoogle Scholar
  19. 19.
    Ammoun S, Cunliffe CH, Allen JC et al (2010) ErbB/HER receptor activation and preclinical efficacy of lapatinib in vestibular schwannoma. Neuro Oncol 12(8):834–843CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Ahmad ZK, Brown CM, Cueva RA, Ryan AF, Doherty JK (2011) ErbB expression, activation, and inhibition with lapatinib and tyrphostin (AG825) in human vestibular schwannomas. Otol Neurotol 32(5):841–847CrossRefPubMedPubMedCentralGoogle Scholar
  21. 21.
    Karajannis MA, Legault G, Hagiwara M et al (2012) Phase II trial of lapatinib in adult and pediatric patients with neurofibromatosis type 2 and progressive vestibular schwannomas. Neuro Oncol 14(9):1163–1170CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Jabbour E, Kantarjian H (2014) Chronic myeloid leukemia: 2014 update on diagnosis, monitoring, and management. Am J Hematol 89(5):547–556CrossRefPubMedGoogle Scholar
  23. 23.
    Cauchi C, Somaiah N, Engstrom PF et al (2012) Evaluation of nilotinib in advanced GIST previously treated with imatinib and sunitinib. Cancer Chemother Pharmacol 69(4):977–982CrossRefPubMedGoogle Scholar
  24. 24.
    Ammoun S, Schmid MC, Triner J, Manley P, Hanemann CO (2011) Nilotinib alone or in combination with selumetinib is a drug candidate for neurofibromatosis type 2. Neuro Oncol 13(7):759–766CrossRefPubMedPubMedCentralGoogle Scholar
  25. 25.
    Blakeley JO, Evans DG, Adler J et al (2012) Consensus recommendations for current treatments and accelerating clinical trials for patients with neurofibromatosis type 2. Am J Med Genet Part A 158A(1):24–41CrossRefPubMedGoogle Scholar
  26. 26.
    Lim DJ, Rubenstein AE, Evans DG et al (2000) Advances in neurofibromatosis 2 (NF2): a workshop report. J Neurogenet 14(2):63–106CrossRefPubMedGoogle Scholar
  27. 27.
    Seferis C, Torrens M, Paraskevopoulou C, Psichidis G (2014) Malignant transformation in vestibular schwannoma: report of a single case, literature search, and debate. J Neurosur 121:160–166Google Scholar
  28. 28.
    Vuletic I, Zhou K, Li H et al (2017) Validation of bevacizumab therapy effect on colon cancer subtypes by using whole body imaging in mice. Mol Imaging Biol. doi: 10.1007/s11307-017-1048-z PubMedGoogle Scholar
  29. 29.
    Ishikura N, Yanagisawa M, Noguchi-Sasaki M et al (2017) Importance of bevacizumab maintenance following combination chemotherapy in human non-small cell lung cancer xenograft models. Anticancer Res 37(2):623–629CrossRefPubMedGoogle Scholar
  30. 30.
    Tai CJ, Wang H, Wang CK et al (2017) Bevacizumab and cetuximab with conventional chemotherapy reduced pancreatic tumor weight in mouse pancreatic cancer xenografts. Clin Exp Med 17(2):141–150CrossRefPubMedGoogle Scholar
  31. 31.
    Nakayama GR, Caton MC, Nova MP, Parandoosh Z (1997) Assessment of the Alamar Blue assay for cellular growth and viability in vitro. J Immunol Methods 204(2):205–208CrossRefPubMedGoogle Scholar
  32. 32.
    Pawaskar DK, Straubinger RM, Fetterly GJ et al (2013) Physiologically based pharmacokinetic models for everolimus and sorafenib in mice. Cancer Chemother Pharmacol 71(5):1219–1229CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Pawaskar DK, Straubinger RM, Fetterly GJ et al (2013) Synergistic interactions between sorafenib and everolimus in pancreatic cancer xenografts in mice. Cancer Chemother Pharmacol 71(5):1231–1240CrossRefPubMedPubMedCentralGoogle Scholar
  34. 34.
    Cejka D, Kuntner C, Preusser M et al (2009) FDG uptake is a surrogate marker for defining the optimal biological dose of the mTOR inhibitor everolimus in vivo. Br J Cancer 100(11):1739–1745CrossRefPubMedPubMedCentralGoogle Scholar
  35. 35.
    O’Reilly T, McSheehy PM, Kawai R et al (2010) Comparative pharmacokinetics of RAD001 (everolimus) in normal and tumor-bearing rodents. Cancer Chemother Pharmacol 65(4):625–639CrossRefPubMedGoogle Scholar
  36. 36.
    Rodriguez FJ, Folpe AL, Giannini C, Perry A (2012) Pathology of peripheral nerve sheath tumors: diagnostic overview and update on selected diagnostic problems. Acta Neuropathol 123(3):295–319CrossRefPubMedPubMedCentralGoogle Scholar
  37. 37.
    Rowe JG, Radatz MW, Walton L, Hampshire A, Seaman S, Kemeny AA (2003) Gamma knife stereotactic radiosurgery for unilateral acoustic neuromas. J Neurol Neurosurg Psychiatry 74(11):1536–1542CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Koontz NA, Wiens AL, Agarwal A et al (2013) SChwannomatosis: the overlooked neurofibromatosis? Am J Roentgenol 200(6):W646–53CrossRefGoogle Scholar
  39. 39.
    Rowe J, Radatz M, Kemeny A (2008) Radiosurgery for type II neurofibromatosis. Prog Neurol Surg 21:176–182CrossRefPubMedGoogle Scholar
  40. 40.
    Gao X, Zhao Y, Stemmer-Rachamimov AO, Liu H, Huang P, Chin S, Selig MK, Plotkin SR, Jain RK, Xu L (2015) Anti-VEGF treatment improves neurological function and augments radiation response in NF2 schwannoma model. Proc Natl Acad Sci USA 112(47):14676–81. doi: 10.1073/pnas.1512570112 CrossRefPubMedPubMedCentralGoogle Scholar
  41. 41.
    Messerli SM, Tang Y, Giovannini M, Bronson R, Weissleder R, Breakefield XO (2002) Detection of spontaneous schwannomas by MRI in a transgenic murine model of neurofibromatosis type 2. Neoplasia 4(6):501–509CrossRefPubMedPubMedCentralGoogle Scholar
  42. 42.
    Jessen WJ, Miller SJ, Jousma E et al (2013) MEK inhibition exhibits efficacy in human and mouse neurofibromatosis tumors. J Clin Invest 123(1):340–347CrossRefPubMedGoogle Scholar
  43. 43.
    Giovannini M, Robanus-Maandag E, van der Valk M et al (2000) Conditional biallelic Nf2 mutation in the mouse promotes manifestations of human neurofibromatosis type 2. Genes Dev 14(13):1617–1630PubMedPubMedCentralGoogle Scholar
  44. 44.
    Messerli SM, Prabhakar S, Tang Y et al (2006) Treatment of schwannomas with an oncolytic recombinant herpes simplex virus in murine models of neurofibromatosis type 2. Hum Gene Ther 17(1):20–30CrossRefPubMedGoogle Scholar
  45. 45.
    Tanaka K, Eskin A, Chareyre F et al (2013) Therapeutic potential of HSP90 inhibition for neurofibromatosis type 2. Clin Cancer Res 19(14):3856–3870CrossRefPubMedPubMedCentralGoogle Scholar
  46. 46.
    Stemmer-Rachamimov AO, Louis DN, Nielsen GP, Antonescu CR, Borowsky AD, Bronson RT, Burns DK, Cervera P, McLaughlin ME, Reifenberger G, Schmale MC, MacCollin M, Chao RC, Cichowski K, Kalamarides M, Messerli SM, McClatchey AI, Niwa-Kawakita M, Ratner N, Reilly KM, Zhu Y, Giovannini M (2004) Comparative pathology of nerve sheath tumors in mouse models and humans. Cancer Res 64(10):3718–3724CrossRefPubMedGoogle Scholar
  47. 47.
    Wagner J, Welzel T, Habermehl D, Debus J, Combs SE (2014) Radiotherapy in patients with vestibular schwannoma and neurofibromatosis type 2: clinical results and review of the literature. Tumori 100(2):189–194. doi: 10.1700/1491.16411 PubMedGoogle Scholar
  48. 48.
    Phi JH, Kim DG, Chung HT, Lee J, Paek SH, Jung HW (2009) Radiosurgical treatment of vestibular schwannomas in patients with neurofibromatosis type 2: tumor control and hearing preservation. Cancer 115(2):390–398. doi: 10.1002/cncr.24036 CrossRefPubMedGoogle Scholar

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

Personalised recommendations