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Antitumor Activity of CEP-751 (KT-6587) on Human Neuroblastoma and Medulloblastoma Xenografts¹

Division of Oncology at The Children’s Hospital of Philadelphia and Department of Pediatrics at the University of Pennsylvania, Philadelphia, Pennsylvania 19104 [A. E. E., K. D. K., N. I., G. M. B.]; Cephalon, Inc., West Chester, Pennsylvania 19380 [A. E. E., K. D. K., N. I., A. M. C., C. A. D., G. M. B.]; and College of Physicians and Surgeons of Columbia University, Division of Pediatric Oncology, New York, New York 10032 [D. J. Y.]

Neuroblastoma (NBL) and medulloblastoma (MBL) are tumors of the neuroectoderm that occur in children. NBL and MBL express Trk family tyrosine kinase receptors, which regulate growth, differentiation, and cell death. CEP-751 (KT-6587), an indolocarbazole derivative, is an inhibitor of Trk family tyrosine kinases at nanomolar concentrations. This study was designed to determine the effect of CEP-751 on the growth of NBL and MBL cell lines as xenografts. 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 two treatment schedules: (a) treatment was started after the tumors were measurable (therapeutic study); or (b) 4–6 days after inoculation, before tumors were palpable (prevention study). CEP-751 was given at 21 mg/kg/dose administered twice a day, 7 days a week; the carrier vehicle was used as a control. In therapeutic studies, a significant difference in tumor size was seen 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 significance, and no inhibition was apparent with DAOY. In prevention studies, CEP-751 showed a modest growth-inhibitory effect on IMR5 (P = 0.062) and CHP-134 (P = 0.049). Furthermore, inhibition of growth was greater in the SY5Y cell line transfected with TrkB compared with the untransfected parent cell line expressing no detectable TrkB. Terminal deoxynucleotidyl transferase-mediated nick end labeling studies showed CEP-751 induced apoptosis in the treated CHP-134 tumors, whereas no evidence of apoptosis was seen in the control tumors. Finally, there was no apparent toxicity identified in any of the treated mice. These results suggest that CEP-751 may be a useful therapeutic agent for NBL or MBL.

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