The aggressive behavior and poor prognosis of pancreatic ductal
adenocarcinoma (PDAC) is associated with an increased expression of many
growth factors 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-derived cell lines, and a dose-dependent
biological response of PDAC cells (in vitro invasiveness) to selective
neurotrophins (Miknyoczki, S. J., et al., Int. J.
Cancer, 81: 417-427, 1999). On the basis of these data, we have evaluated the therapeutic potential of inhibiting
neurotrophin-Trk interactions using a selective and potent Trk
tyrosine kinase inhibitor (CEP-701) in several preclinical models of human PDAC.
CEP-701 is currently approved for clinical trials within the United States We demonstrate that
CEP-701 administration
at 10 mg/kg s.c. b.i.d. 5 days a week for 21-28 days inhibited
tumor growth in a statistically significant manner in Panc-1, AsPc-1, BxPc-3, Colo 357, and MiaPaCa2 s.c. xenografts in athymic nude mice compared with vehicle-treated controls. Reductions in
tumor growth volume of 50-70% relative to vehicle-treated controls were observed in xenografts responsive to
CEP-701 administration. Significant reductions of in vivo PDAC
tumor invasiveness were likewise observed in four of six CEP-701-treated rat tracheal xenografts implanted s.c. in athymic nude mice. The antitumor efficacy of
CEP-701 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 potential therapeutic agent in the treatment or management of PDAC.