Tyrosine Kinase Inhibitors

c-kit has been shown to be expressed in some neuroblastoma cell lines, preferentially those with MYCN amplification, and therefore growth inhibitory activity of Gleevec has been demonstrated, both in vitro (Vitali et al. 2003) and in xenograft models (Beppu et al. 2004),leading to testing in pediatric phase-II studies. Another tyrosine kinase inhibitor in clinical testing is CEP-701, a selective inhibitor of several cell-surface receptor-linked tyrosine kinases, with highest affinity and specificity for the Trk receptors. The BDNF/TrkB signaling pathway is a key autocrine survival mechanism for neuroblastomas in patients with high-risk disease, where TrkB is over-expressed (Suzuki et al. 1993; Nakagawara et al. 1994). CEP-701 has high oral bioavailability and potently inhibits all three Trk tyrosine kinases with IC50 values of 3±1nM (George et al. 1999). CEP-701 also inhibits VEGFR and PDGFR kinase activity, and inhibits the hematopoietic receptor, FLT-3, but has little inhibitory activity against other receptor tyrosine kinases (e.g., EGFR kinase). Targeted inhibition of this pathway has been proven efficacious in preclinical models of human neuroblastoma (Ho et al. 2002; Evans et al. 1999). Ongoing clinical trials of CEP-701 in adult patients with refractory acute myeloid leukemia have shown the drug to be relatively well tolerated, an MTD of 60 mg twice daily has been defined, and biologic and clinical activity has been shown (Smith et al. 2004). A phase-I trial in children with refractory neuroblastoma is ongoing in NANT.

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