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

Gunnar Johansson, Yonatan Y. Mahller, Margaret H. Collins, Mi Ok Kim, Takahiro Nobukuni, John Perentesis, Timothy P. Cripe, Heidi A. Lane, Sara C. Kozma, George Thomas, Nancy Ratner

研究成果: Article査読

101 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)1237-1245
ページ数9
ジャーナルMolecular Cancer Therapeutics
7
5
DOI
出版ステータスPublished - 2008
外部発表はい

ASJC Scopus subject areas

  • 腫瘍学
  • 癌研究

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