Human Schwannomas Express Activated Platelet-Derived Growth Factor Receptors and c-kit and Are Growth Inhibited by Gleevec (Imatinib Mesylate)

¹Arthur and Sonia Labatt Brain Tumor Research Centre, The Hospital for Sick Children Research Institute, University of Toronto; ²Division of Neuropathology, Department of Pathology, Toronto General Hospital, and ³Division of Neurosurgery, Department of Surgery, Toronto Western Hospital, University Health Network, University of Toronto, Toronto, Ontario, Canada

^* To whom correspondence should be addressed. E-mail: abhijit.guha{at}uhn.on.ca.

	Abstract

Schwannomas, although benign, can be fatal or give rise to significant morbidity due to an unpredictable growth rate. They can reoccur after surgery or radiation, current treatments each with significant inherent risks. These risks are further amplified in neurofibromatosis type 2 (NF2), a germ line predisposition syndrome characterized by multiple schwannomas, underlying the need for biological targeted therapies. Gleevec (STI571, imatinib mesylate), in addition to the bcr-abl oncogene in chronic myelogenous leukemia, inhibits c-kit and platelet-derived growth factor receptor (PDGFR) signaling, thereby expanding its use to several malignant and benign human diseases. In the present study, we show that human sporadic and NF2-associated schwannomas have increased expression along with activation of PDGFR-, PDGFR-, and c-kit receptors, compared with normal or traumatic nerve. Using the human NF2-null HEI-193 schwannoma cell line, Gleevec inhibited schwannoma viability, proliferation, and anchorage-independent growth, as well as induced apoptosis in a dose-dependent manner (IC₅₀ 5–10 µmol/L). These antitumorigenic effects were correlated to inhibition of PDGFR-, PDGFR-, and c-kit activation/phosphorylation and major downstream signaling pathways. Lack of robust xenograft or transgenic models of schwannomas prevents extension of these studies in vivo. However, the established long track record and tolerable toxicity of Gleevec already in clinical use and our preclinical data lead us to propose that Gleevec should be evaluated in human schwannomas with shown progressive growth. [Cancer Res 2009;69(12):5099–107]

Key Words: Gleevec, Schwannoma, Neurofibromitosis type-2, PDGFR- and PDGFR-, c-KIT