A Monoclonal Antibody Against β1 Integrin Inhibits Proliferation and Increases Survival in an Orthotopic Model of High-Grade Meningioma
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.
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.
- 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.Preusser M, Brastianos PK, Mawrin C. Advances in meningioma genetics: novel therapeutic opportunities. Nat Rev Neurol. 2018;14(2):106–15.Google Scholar
- 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.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.Mawrin C, Perry A. Pathological classification and molecular genetics of meningiomas. J Neurooncol. 2010;99(3):379–91.Google Scholar
- 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.Wen PY, Quant E, Drappatz J, Beroukhim R, Norden AD. Medical therapies for meningiomas. J Neurooncol. 2010;99(3):365–78.Google Scholar
- 8.Desgrosellier JS, Cheresh DA. Integrins in cancer: biological implications and therapeutic opportunities. Nat Rev Cancer. 2010;10(1):9–22.Google Scholar
- 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.Raab-Westphal S, Marshall JF, Goodman SL. Integrins as therapeutic targets: successes and cancers. Cancers (Basel). 2017;9(9):110.Google Scholar
- 11.Avraamides CJ, Garmy-Susini B, Varner JA. Integrins in angiogenesis and lymphangiogenesis. Nat Rev Cancer. 2008;8(8):604–17.Google Scholar
- 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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.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.Kalamarides M, Peyre M, Giovannini M. Meningioma mouse models. J Neurooncol. 2010;99(3):325–31.Google Scholar
- 34.Mawrin C. Animal models of meningiomas. Chin Clin Oncol. 2017;6(Suppl 1):S6.Google Scholar
- 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.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.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.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.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.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.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.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