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 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.
Miknyoczki
S J
SJ
Department of Oncology, Cephalon, Inc., West Chester, Pennsylvania 19380, USA.
Chang
H
H
Klein-Szanto
A
A
Dionne
C A
CA
Ruggeri
B A
BA
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001835:Body Weight / Q000187:drug effects; D002227:Carbazoles / Q000627:therapeutic use*; D004354:Drug Screening Assays, Antitumor; D005260:Female; D005663:Furans; D006801:Humans; D007150:Immunohistochemistry; D007211:Indoles; D051379:Mice; D008819:Mice, Nude; D009361:Neoplasm Invasiveness / Q000473:pathology; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D051381:Rats; D020917:Receptor, trkA / Q000037:antagonists & inhibitors*; D013997:Time Factors; D014132:Trachea / Q000187:drug effects / Q000473:pathology; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D002227:Carbazoles; D005663:Furans; D007211:Indoles; C119379:lestaurtinib; D020917:Receptor, trkA