Lestaurtinib enhances the antitumor efficacy of chemotherapy in murine xenograft models of neuroblastoma.
OBJECTIVE
Neuroblastoma, a common pediatric tumor of the sympathetic nervous system, is characterized by clinical heterogeneity. The Trk family neurotrophin receptors play an important role in this behavior. Expression of TrkA is associated with favorable clinical features and outcome, whereas TrkB expression is associated with an unfavorable prognosis. We wanted to determine if the Trk-selective inhibitor lestaurtinib had therapeutic efficacy in a preclinical neuroblastoma model.


METHODS
We performed intervention trials of lestaurtinib alone or in combination with other agents in TrkB-overexpressing neuroblastoma xenograft models.


RESULTS
Lestaurtinib alone significantly inhibited tumor growth compared to vehicle-treated animals [P = 0.0004 for tumor size and P = 0.011 for event-free survival (EFS)]. Lestaurtinib also enhanced the antitumor efficacy of the combinations of topotecan plus cyclophosphamide (P < 0.0001 for size and P < 0.0001 for EFS) or irinotecan plus temozolomide (P = 0.011 for size and P = 0.012 for EFS). There was no additive benefit of combining either 13-cis-retinoic acid or fenretinide with lestaurtinib compared to lestaurtinib alone. There was dramatic growth inhibition combining lestaurtinib with bevacizumab (P < 0.0001), but this combination had substantial systemic toxicity.


CONCLUSIONS
We show that lestaurtinib can inhibit the growth of neuroblastoma both in vitro and in vivo and can substantially enhance the efficacy of conventional chemotherapy, presumably by inhibition of the Trk/brain-derived neurotrophic factor autocrine survival pathway. It may also enhance the efficacy of selected biological agents, but further testing is required to rule out unanticipated toxicities. Our data support the incorporation of Trk inhibitors, such as lestaurtinib, in clinical trials of neuroblastoma or other tumors relying on Trk signaling pathways for survival.
Iyer
Radhika
R
Division of Oncology and Biostatistics and Data Management Core, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania 19104, USA.
Evans
Audrey E
AE
Qi
Xiaoxue
X
Ho
Ruth
R
Minturn
Jane E
JE
Zhao
Huaqing
H
Balamuth
Naomi
N
Maris
John M
JM
Brodeur
Garrett M
GM
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D061067:Antibodies, Monoclonal, Humanized; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D000068258:Bevacizumab; D002166:Camptothecin / Q000008:administration & dosage / Q000031:analogs & derivatives; D002227:Carbazoles / Q000627:therapeutic use*; D003520:Cyclophosphamide / Q000008:administration & dosage; D003606:Dacarbazine / Q000008:administration & dosage / Q000031:analogs & derivatives; D004789:Enzyme Activation / Q000187:drug effects; D005663:Furans; D006801:Humans; D000077146:Irinotecan; D051379:Mice; D008819:Mice, Nude; D009447:Neuroblastoma / Q000188:drug therapy*; D020813:Receptor, trkB / Q000187:drug effects / Q000378:metabolism; D000077204:Temozolomide; D019772:Topotecan / Q000008:administration & dosage; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D002227:Carbazoles; D005663:Furans; D000068258:Bevacizumab; D000077146:Irinotecan; D003606:Dacarbazine; D019772:Topotecan; D003520:Cyclophosphamide; C119379:lestaurtinib; D020813:Receptor, trkB; D002166:Camptothecin; D000077204:Temozolomide