Integrin inhibition as a potential target for invasive meningiomas.

Abstract

e22140 Background: Meningiomas are frequent intracranial tumors, which may show high rates of tumor recurrence after surgery. Additionally, a number of meningiomas show aggressive clinical behaviour with significant reduction of patient´s survival. In the present study, the impact of cilengitide, an integrin inhibitor, on migration, proliferation and radiosensitization of meningioma cells was evaluated. Methods: We analyzed integrin expression in tissue microarray samples and the anti-meningioma properties of cilengitide in vitro using different meningioma cell lines including pairs with knockdown of NF2, and tested the substance in subcutaneous and intracranial orthotopic nude mice models. Results: The predominantly expressed integrin in the tumor cells was αvβ5, while αvβ3 was mainly restricted to tumor blood vessels. One µM cilengitide was sufficient to significantly inhibit meningioma cell migration and invasion in vitro. On the other hand, even high doses of the drug resulted in only mildly reduced proliferation/survival of the cells, although the effects on cell survival were improved by irradiation. A daily dosage of up to 75 mg/kg did not affect tumor volumes in both mouse models. However, a combination of 75 mg/kg cilengitide daily and irradiation (2 x 5 Gy) led to a stronger reduction of MRI estimated tumor volumes in the intracranial model (67%, p<0.01), as compared to the corresponding reduction reached by irradiation alone (55%, p<0.05). Conclusions: These data show that the integrin inhibitor has mild cytostatic properties in meningioma cells, but strongly inhibits cell migration/invasion. In combination with radiotherapy it may help to further reduce meningioma tumor recurrence.