Abstract | PURPOSE:
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. EXPERIMENTAL DESIGN: We performed intervention trials of lestaurtinib alone or in combination with other agents in TrkB-overexpressing neuroblastoma xenograft models. RESULTS: 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.
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Authors | Radhika Iyer, Audrey E Evans, Xiaoxue Qi, Ruth Ho, Jane E Minturn, Huaqing Zhao, Naomi Balamuth, John M Maris, Garrett M Brodeur |
Journal | Clinical cancer research : an official journal of the American Association for Cancer Research
(Clin Cancer Res)
Vol. 16
Issue 5
Pg. 1478-85
(Mar 01 2010)
ISSN: 1557-3265 [Electronic] United States |
PMID | 20179224
(Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
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Chemical References |
- Antibodies, Monoclonal
- Antibodies, Monoclonal, Humanized
- Carbazoles
- Furans
- Bevacizumab
- Irinotecan
- Dacarbazine
- Topotecan
- Cyclophosphamide
- lestaurtinib
- Receptor, trkB
- Camptothecin
- Temozolomide
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Topics |
- Animals
- Antibodies, Monoclonal
(administration & dosage)
- Antibodies, Monoclonal, Humanized
- Antineoplastic Combined Chemotherapy Protocols
(therapeutic use)
- Bevacizumab
- Camptothecin
(administration & dosage, analogs & derivatives)
- Carbazoles
(therapeutic use)
- Cyclophosphamide
(administration & dosage)
- Dacarbazine
(administration & dosage, analogs & derivatives)
- Enzyme Activation
(drug effects)
- Furans
- Humans
- Irinotecan
- Mice
- Mice, Nude
- Neuroblastoma
(drug therapy)
- Receptor, trkB
(drug effects, metabolism)
- Temozolomide
- Topotecan
(administration & dosage)
- Xenograft Model Antitumor Assays
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