A Monoclonal Antibody Against β1 Integrin Inhibits Proliferation and Increases Survival in an Orthotopic Model of High-Grade Meningioma

  • Fares Nigim
  • Juri Kiyokawa
  • Alessandra Gurtner
  • Yoichiro Kawamura
  • Lingyang Hua
  • Ekkehard M. Kasper
  • Priscilla K. Brastianos
  • Daniel P. Cahill
  • Samuel D. Rabkin
  • Robert L. Martuza
  • W. Shawn Carbonell
  • Hiroaki WakimotoEmail author
Original Research Article



High-grade meningiomas (HGMs; World Health Organization [WHO] classification grade II and III) have high relapse rates and poor clinical outcomes despite surgery and radiation treatments. No effective medical therapy currently exists for HGMs, and developing novel therapeutic strategies depends on the identification of molecular drivers. In cancer, β1 integrin enhances malignant characteristics, including proliferation, invasion, and drug resistance.


We conducted this study to investigate whether β1 integrin could be a therapeutic target in HGMs.

Patients and Methods

Expression of β1 integrin was examined in gene array datasets, with proteomics of clinical meningioma specimens, and in patient-derived HGM xenografts. Anti-tumor activity of OS2966, a first-in-class humanized antagonizing monoclonal antibody against β1 integrin, was tested in vitro and in vivo using an orthotopic mouse model of patient-derived malignant meningioma.


β1 integrin was expressed in meningiomas of all WHO grades and two xenografts tested. In vitro, OS2966 suppressed the viability of NF2-deficient MN3 sphere cells and NF2-wild-type IOMM-Lee malignant meningioma cells only when plated on laminin-coated plastic. While OS2966 decreased phosphorylation of ERK1/2 in both MN3 cells and laminin-grown IOMM-Lee cells, OS2966 only affected the phosphorylation of FAK (Tyr397) in MN3, and of Akt (Ser473) in IOMM-Lee cells, respectively, indicating differential pathway inhibition. Systemic administration of OS2966 in mice bearing orthotopic MN3 HGMs inhibited HGM cell proliferation and significantly extended overall survival of the treated mice.


β1 Integrin may be a therapeutic target in HGMs, and further preclinical and clinical development of OS2966 for HGM therapy is warranted.


Compliance with Ethical Standards


This work was supported by Meningioma Mommas (HW and RLM).

Conflict of interest

W. Shawn Carbonell is a co-founder, Director, and CEO of OncoSynergy, Inc. Daniel P. Cahill serves as a consultant for Merck and Lilly. Priscilla K. Brastianos serves as a consultant for Angiochem, Tesaro, and Lilly; has received speaker’s honoraria from Merck and Genentech-Roche; and has received institutional funding from Pfizer and Merck. Fares Nigim, Juri Kiyokawa, Alessandra Gurtner, Yoichiro Kawamura, Lingyang Hua, Ekkehard M. Kasper, Samuel D. Rabkin, Robert L. Martuza, and Hiroaki Wakimoto declare that they have no conflicts of interest that might be relevant to the contents of this manuscript.

Ethical approval

All work with animals was conducted with the approval of the IACUC at MGH, and followed all applicable international, national and institutional guidelines for the care and use of animals. The procedures involving human excess materials to establish xenograft models were performed under Institutional Review Board (IRB) approval at MGH in accordance with the ethical standards of the institutional and/or national research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. The IRB protocol exempted informed consent.

Supplementary material

11523_2019_654_MOESM1_ESM.pdf (253 kb)
Supplementary material 1 (PDF 252 kb)


  1. 1.
    Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, editors. WHO classification of tumours of the central nervous system. 4th ed. Lyon: IARC; 2016 (revised).Google Scholar
  2. 2.
    Preusser M, Brastianos PK, Mawrin C. Advances in meningioma genetics: novel therapeutic opportunities. Nat Rev Neurol. 2018;14(2):106–15.Google Scholar
  3. 3.
    Ostrom QT, Gittleman H, Truitt G, Boscia A, Kruchko C, Barnholtz-Sloan JS. CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2011–2015. Neuro Oncol. 2018;20 Suppl 4:iv1–86.Google Scholar
  4. 4.
    Kshettry VR, Ostrom QT, Kruchko C, Al-Mefty O, Barnett GH, Barnholtz-Sloan JS. Descriptive epidemiology of World Health Organization grades II and III intracranial meningiomas in the United States. Neuro Oncol. 2015;17(8):1166–73.Google Scholar
  5. 5.
    Mawrin C, Perry A. Pathological classification and molecular genetics of meningiomas. J Neurooncol. 2010;99(3):379–91.Google Scholar
  6. 6.
    Buttrick S, Shah AH, Komotar RJ, Ivan ME. Management of atypical and anaplastic meningiomas. Neurosurg Clin N Am. 2016;27(2):239–47.Google Scholar
  7. 7.
    Wen PY, Quant E, Drappatz J, Beroukhim R, Norden AD. Medical therapies for meningiomas. J Neurooncol. 2010;99(3):365–78.Google Scholar
  8. 8.
    Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10(1):9–22.Google Scholar
  9. 9.
    Hamidi H, Pietila M, Ivaska J. The complexity of integrins in cancer and new scopes for therapeutic targeting. Br J Cancer. 2016;115(9):1017–23.Google Scholar
  10. 10.
    Raab-Westphal S, Marshall JF, Goodman SL. Integrins as therapeutic targets: successes and cancers. Cancers (Basel). 2017;9(9):110.Google Scholar
  11. 11.
    Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer. 2008;8(8):604–17.Google Scholar
  12. 12.
    Jahangiri A, Aghi MK, Carbonell WS. Beta1 integrin: critical path to antiangiogenic therapy resistance and beyond. Cancer Res. 2014;74(1):3–7.Google Scholar
  13. 13.
    Carbonell WS, DeLay M, Jahangiri A, Park CC, Aghi MK. Beta1 integrin targeting potentiates antiangiogenic therapy and inhibits the growth of bevacizumab-resistant glioblastoma. Cancer Res. 2013;73(10):3145–54.Google Scholar
  14. 14.
    Beschet I, Brunon J, Scoazec JY, Mosnier JF. Expression of beta1 and beta4 integrins in normal arachnoid membrane and meningiomas. Cancer. 1999;86(12):2649–58.Google Scholar
  15. 15.
    Figarella-Branger D, Roche PH, Daniel L, Dufour H, Bianco N, Pellissier JF. Cell-adhesion molecules in human meningiomas: correlation with clinical and morphological data. Neuropathol Appl Neurobiol. 1997;23(2):113–22.Google Scholar
  16. 16.
    Gogineni VR, Nalla AK, Gupta R, Gujrati M, Klopfenstein JD, Mohanam S, et al. alpha3beta1 integrin promotes radiation-induced migration of meningioma cells. Int J Oncol. 2011;38(6):1615–24.Google Scholar
  17. 17.
    Salehi F, Jalali S, Alkins R, Lee JI, Lwu S, Burrell K, et al. Proteins involved in regulating bone invasion in skull base meningiomas. Acta Neurochir (Wien). 2013;155(3):421–7.Google Scholar
  18. 18.
    Poulikakos PI, Xiao GH, Gallagher R, Jablonski S, Jhanwar SC, Testa JR. Re-expression of the tumor suppressor NF2/merlin inhibits invasiveness in mesothelioma cells and negatively regulates FAK. Oncogene. 2006;25(44):5960–8.Google Scholar
  19. 19.
    Shapiro IM, Kolev VN, Vidal CM, Kadariya Y, Ring JE, Wright Q, et al. Merlin deficiency predicts FAK inhibitor sensitivity: a synthetic lethal relationship. Sci Transl Med. 2014;6(237):237ra68.Google Scholar
  20. 20.
    Park CC, Zhang H, Pallavicini M, Gray JW, Baehner F, Park CJ, et al. Beta1 integrin inhibitory antibody induces apoptosis of breast cancer cells, inhibits growth, and distinguishes malignant from normal phenotype in three dimensional cultures and in vivo. Cancer Res. 2006;66(3):1526–35.Google Scholar
  21. 21.
    Kenny HA, Chiang CY, White EA, Schryver EM, Habis M, Romero IL, et al. Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion. J Clin Investig. 2014;124(10):4614–28.Google Scholar
  22. 22.
    Nitta H, Yamashima T, Yamashita J, Kubota T. An ultrastructural and immunohistochemical study of extracellular matrix in meningiomas. Histol Histopathol. 1990;5(3):267–74.Google Scholar
  23. 23.
    Nigim F, Esaki S, Hood M, Lelic N, James MF, Ramesh V, et al. A new patient-derived orthotopic malignant meningioma model treated with oncolytic herpes simplex virus. Neuro Oncol. 2016;18(9):1278–87.Google Scholar
  24. 24.
    Lee WH. Characterization of a newly established malignant meningioma cell line of the human brain: IOMM-Lee. Neurosurgery. 1990;27(3):389–95 (discussion 96).Google Scholar
  25. 25.
    Lee Y, Liu J, Patel S, Cloughesy T, Lai A, Farooqi H, et al. Genomic landscape of meningiomas. Brain Pathol. 2010;20(4):751–62.Google Scholar
  26. 26.
    Clark VE, Harmanci AS, Bai H, Youngblood MW, Lee TI, Baranoski JF, et al. Recurrent somatic mutations in POLR2A define a distinct subset of meningiomas. Nat Genet. 2016;48(10):1253–9.Google Scholar
  27. 27.
    Harmanci AS, Youngblood MW, Clark VE, Coskun S, Henegariu O, Duran D, et al. Integrated genomic analyses of de novo pathways underlying atypical meningiomas. Nat Commun. 2017;8:14433.Google Scholar
  28. 28.
    Chen HC, Appeddu PA, Isoda H, Guan JL. Phosphorylation of tyrosine 397 in focal adhesion kinase is required for binding phosphatidylinositol 3-kinase. J Biol Chem. 1996;271(42):26329–34.Google Scholar
  29. 29.
    Mitra SK, Schlaepfer DD. Integrin-regulated FAK-Src signaling in normal and cancer cells. Curr Opin Cell Biol. 2006;18(5):516–23.Google Scholar
  30. 30.
    Schaller MD, Hildebrand JD, Shannon JD, Fox JW, Vines RR, Parsons JT. Autophosphorylation of the focal adhesion kinase, pp125FAK, directs SH2-dependent binding of pp60src. Mol Cell Biol. 1994;14(3):1680–8.Google Scholar
  31. 31.
    Schlager C, Korner H, Krueger M, Vidoli S, Haberl M, Mielke D, et al. Effector T-cell trafficking between the leptomeninges and the cerebrospinal fluid. Nature. 2016;530(7590):349–53.Google Scholar
  32. 32.
    Weller RO, Sharp MM, Christodoulides M, Carare RO, Mollgard K. The meninges as barriers and facilitators for the movement of fluid, cells and pathogens related to the rodent and human CNS. Acta Neuropathol. 2018;135(3):363–85.Google Scholar
  33. 33.
    Kalamarides M, Peyre M, Giovannini M. Meningioma mouse models. J Neurooncol. 2010;99(3):325–31.Google Scholar
  34. 34.
    Mawrin C. Animal models of meningiomas. Chin Clin Oncol. 2017;6(Suppl 1):S6.Google Scholar
  35. 35.
    Mei Y, Bi WL, Greenwald NF, Agar NY, Beroukhim R, Dunn GP, et al. Genomic profile of human meningioma cell lines. PLoS ONE. 2017;12(5):e0178322.Google Scholar
  36. 36.
    Choy W, Kim W, Nagasawa D, Stramotas S, Yew A, Gopen Q, et al. The molecular genetics and tumor pathogenesis of meningiomas and the future directions of meningioma treatments. Neurosurg Focus. 2011;30(5):E6.Google Scholar
  37. 37.
    Lomas J, Bello MJ, Arjona D, Alonso ME, Martinez-Glez V, Lopez-Marin I, et al. Genetic and epigenetic alteration of the NF2 gene in sporadic meningiomas. Genes Chromosomes Cancer. 2005;42(3):314–9.Google Scholar
  38. 38.
    Hersey P, Sosman J, O’Day S, Richards J, Bedikian A, Gonzalez R, et al. A randomized phase 2 study of etaracizumab, a monoclonal antibody against integrin alpha(v)beta(3), + or − dacarbazine in patients with stage IV metastatic melanoma. Cancer. 2010;116(6):1526–34.Google Scholar
  39. 39.
    Hirata E, Girotti MR, Viros A, Hooper S, Spencer-Dene B, Matsuda M, et al. Intravital imaging reveals how BRAF inhibition generates drug-tolerant microenvironments with high integrin beta1/FAK signaling. Cancer Cell. 2015;27(4):574–88.Google Scholar
  40. 40.
    Lesniak D, Xu Y, Deschenes J, Lai R, Thoms J, Murray D, et al. Beta1-integrin circumvents the antiproliferative effects of trastuzumab in human epidermal growth factor receptor-2-positive breast cancer. Cancer Res. 2009;69(22):8620–8.Google Scholar
  41. 41.
    Park CC, Zhang HJ, Yao ES, Park CJ, Bissell MJ. Beta1 integrin inhibition dramatically enhances radiotherapy efficacy in human breast cancer xenografts. Cancer Res. 2008;68(11):4398–405.Google Scholar
  42. 42.
    Sethi T, Rintoul RC, Moore SM, MacKinnon AC, Salter D, Choo C, et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat Med. 1999;5(6):662–8.Google Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  • Fares Nigim
    • 1
  • Juri Kiyokawa
    • 1
  • Alessandra Gurtner
    • 1
  • Yoichiro Kawamura
    • 1
  • Lingyang Hua
    • 1
    • 2
  • Ekkehard M. Kasper
    • 3
  • Priscilla K. Brastianos
    • 4
    • 5
  • Daniel P. Cahill
    • 1
  • Samuel D. Rabkin
    • 1
  • Robert L. Martuza
    • 1
  • W. Shawn Carbonell
    • 6
  • Hiroaki Wakimoto
    • 1
    Email author
  1. 1.Department of Neurosurgery, Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  2. 2.Department of Neurosurgery, Huashan HospitalShanghai Medical College, Fudan UniversityShanghaiChina
  3. 3.Division of Neurosurgery, Hamilton General HospitalMcMaster UniversityHamiltonCanada
  4. 4.Division of Neuro-Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  5. 5.Division of Hematology and Oncology, Massachusetts General HospitalHarvard Medical SchoolBostonUSA
  6. 6.OncoSynergy, Inc.GreenwichUSA

Personalised recommendations