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Research Articles: Therapeutics, Targets, and Development

Effective in vivo targeting of the mammalian target of rapamycin pathway in malignant peripheral nerve sheath tumors

Divisions of ¹ Experimental Hematology, ² Hematology/Oncology, and ³ Pathology and Laboratory Medicine; and ⁴ Center for Epidemiology and Biostatistics, Department of Pediatrics; ⁵ Genome Research Institute, University of Cincinnati, Cincinnati, Ohio; and ⁶ Novartis Institutes for BioMedical Research, Oncology Basel, Novartis Pharma AG, Basel, Switzerland

Requests for reprints: Nancy Ratner, Division of Experimental Hematology, Cincinnati Children's Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, OH 45229. Phone: 513-636-9469; Fax: 513-636-3549. E-mail: nancy.ratner{at}cchmc.org

Abstract

Malignant peripheral nerve sheath tumors (MPNST) are chemoresistant sarcomas with poor 5-year survival that arise in patients with neurofibromatosis type 1 (NF1) or sporadically. We tested three drugs for single and combinatorial effects on collected MPNST cell lines and in MPNST xenografts. The mammalian target of rapamycin complex 1 inhibitor RAD001 (Everolimus) decreased growth 19% to 60% after 4 days of treatment in NF1 and sporadic-derived MPNST cell lines. Treatment of subcutaneous sporadic MPNST cell xenografts with RAD001 significantly, but transiently, delayed tumor growth, and decreased vessel permeability within xenografts. RAD001 combined with the epidermal growth factor receptor tyrosine kinase inhibitor erlotinib caused additional inhibitory effects on growth and apoptosis in vitro, and a small but significant additional inhibitory effect on MPNST growth in vivo that were larger than the effects of RAD001 with doxorubicin. RAD001 plus erlotinib, in vitro and in vivo, reduced phosphorylation of AKT and total AKT levels, possibly accounting for their additive effect. The results support the consideration of RAD001 therapy in NF1 patient and sporadic MPNST. The preclinical tests described allow rapid screening strata for drugs that block MPNST growth, prior to tests in more complex models, and should be useful to identify drugs that synergize with RAD001. [Mol Cancer Ther 2008;7(5):1237–45]

Grant support: Translational Research Initiative of Cincinnati Children's Hospital Research Foundation and R01 NS28840-17 (N. Ratner).

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

⁷ Supplementary material for this article is available at Molecular Cancer Therapeutics Online (http://mct.aacrjournals.org/).

Received 11/27/07; revised 1/29/08; accepted 2/18/08.