The Trk tyrosine kinase inhibitor CEP-701 (KT-5555) exhibits significant antitumor efficacy in preclinical xenograft models of human pancreatic ductal adenocarcinoma

The aggressive behavior and poor prognosis of pancreatic ductal adenocarcin oma (PDAC) is associated with an increased expression of many growth factor s and their cognate receptors, We have previously demonstrated the aberrant expression of the Trk receptors (Trks A, B, and C), enhanced tumor stromal expression of neurotrophins in primary PDAC specimens and human PDAC-deriv ed cell lines, and a dose-dependent biological response of PDAC cells (in v itro invasiveness) to selective neurotrophins (Miknyoczki, S. J., et al., I nt. J. Cancer, 81: 417-427, 1999). On the basis of these data, we have eval uated the therapeutic potential of inhibiting neurotrophin-Trk interactions using a selective and potent Trk tyrosine kinase inhibitor (CEP-701) in se veral preclinical models of human PDAC, CEP-701 is currently approved for c linical trials within the United States We demonstrate that CEP-701 adminis tration at 10 mg/kg s.c. b.i.d. 5 days a week for 21-28 days inhibited tumo r growth in a statistically significant manner in Panc-1, AsPc-1, BxPc-3, C olo 357, and MiaPaCa2 s.c. xenografts in athymic nude mice compared with ve hicle-treated controls, Reductions in tumor growth volume of 50-70% relativ e to vehicle-treated controls were observed in xenografts responsive to CEP -701 administration. Significant reductions of in vivo PDAC tumor invasiven ess were likewise observed in four of six CEP-701-treated rat tracheal xeno grafts implanted s.c. in athymic nude mice. The antitumor efficacy of CEP-7 01 was observed in the absence of pronounced morbidity or toxicity in vivo. Taken together, these data suggest that CEP-701 may be effective as a pote ntial therapeutic agent in the treatment or management of PDAC.