Antitumor activity of CEP-751 (KT-6587) on human neuroblastoma and medulloblastoma xenografts

Neuroblastoma (NBL) and medulloblastoma (MBL) are tumors of the neuroectode rm that occur in children, NBL and MBL express Trk family tyrosine kinase r eceptors, which regulate growth, differentiation, and cell death. CEP-751 ( KT-6587), an indolocarbazole derivative, is an inhibitor of Trk family tyro sine kinases at nanomolar concentrations. This study was designed to determ ine the effect of CEP-751 on the growth of NEL and MBL cell lines as xenogr afts. In vivo studies were conducted on four NBL cell lines (IMR-5, CHP-134 , NBL-S, and SY5Y) and three MBL cell lines (D283, D341, and DAOY) using tw o treatment schedules: (a) treatment was started after the tumors were meas urable (therapeutic study); or (b) 4-6 days after inoculation, before tumor s were palpable (prevention study). CEP-751 was given at 21 mg/kg/dose admi nistered twice a day, 7 days a week; the carrier vehicle was used as a cont rol, In therapeutic studies, a significant difference in tumor size was see n between treated and control animals with IMR-5 on day 8 (P = 0.01), NBL-S on day 17 (P = 0.016), and CHP-134 on day 15 (P = 0.034), CEP-751 also had a significant growth-inhibitory effect on the MBL Line D283 (on day 39, P = 0.031), Inhibition of tumor growth of D341 did not reach statistical sign ificance, and no inhibition was apparent with DAOY, In prevention studies, CEP-751 showed a modest growth-inhibitory effect on IMR5 (P = 0.062) and CH P-134 (P = 0.049), Furthermore, inhibition of growth was greater in the SY5 Y cell line transfected with TrkB compared with the untransfected parent ce ll line expressing no detectable TrkB, Terminal deoxynucleotidyl transferas e-mediated nick end labeling studies showed CEP-751 induced apoptosis in th e treated CHP-134 tumors, whereas no evidence of apoptosis was seen in the control tumors. Finally, there was no apparent toxicity identified in any o f the treated mice. These results suggest that CEP-751 may be a useful ther apeutic agent for NBL or MBL.