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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

Abstract

Background

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.

Objective

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.

Results

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.

Conclusions

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

Notes

Compliance with Ethical Standards

Funding

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)

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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

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