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-alpha,
PDGFR-beta, 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 (IC(50) 5-10 micromol/L). These antitumorigenic effects were correlated to inhibition of PDGFR-alpha,
PDGFR-beta, 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.