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Preclinical evaluation of the combination of mTOR and proteasome inhibitors with radiotherapy in malignant peripheral nerve sheath tumors

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Abstract

About one half of malignant peripheral nerve sheath tumors (MPNST) have Neurofibromin 1 (NF1) mutations. NF1 is a tumor suppressor gene essential for negative regulation of RAS signaling. Survival for MPNST patients is poor and we sought to identify an effective combination therapy. Starting with the mTOR inhibitors rapamycin and everolimus, we screened for synergy in 542 FDA approved compounds using MPNST cells with a native NF1 loss in both alleles. We further analyzed the cell cycle and signal transduction. In vivo growth effects of the drug combination with local radiation therapy (RT) were assessed in MPNST xenografts. The synergistic combination of mTOR inhibitors with bortezomib yielded a reduction in MPNST cell proliferation. The combination of mTOR inhibitors and bortezomib also enhanced the anti-proliferative effect of radiation in vitro. In vivo, the combination of mTOR inhibitor (everolimus) and bortezomib with RT decreased tumor growth and proliferation, and augmented apoptosis. The combination of approved mTOR and proteasome inhibitors with radiation showed a significant reduction of tumor growth in an animal model and should be investigated and optimized further for MPNST therapy.

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Acknowledgments

The NF90.8 and ST88-14 cells were donated by Dr Michael Tainsky (Wayne University, Detroit, MI) and T265-2C was donated by Dr Steven Porcelli (Albert Einstein College of Medicine, Bronx, NY). The authors thank for Dr William Tadeu Lara Festuccia for their valuable suggestions to improve the quality of paper. Funding was provided by the U.S. Department of Defense grant W81XWH-10-1-0387 (GJR), the Virginia and D.K. Ludwig Fund for Cancer Research, the Irving J Sherman Research Professorship (GJR) and Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES), graduate student’s scholarship grant (BEX-5939/11-9) to ASY.

Conflict of interest

The authors declare no conflict of interest that would prejudice the impartiality of this scientific work.

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Authors and Affiliations

  1. Department of Neurosurgery, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Johns Hopkins University, Koch Building Rm. 257, 1550 Orleans Street, Baltimore, MD, 21231, USA

    A. S. Yamashita, G. S. Baia, J. S. Y. Ho, G. L. Gallia, A. J. Belzberg & G. J. Riggins

  2. Department of Radiation Oncology, Johns Hopkins University School of Medicine, Johns Hopkins Hospital, Johns Hopkins University, Baltimore, MD, USA

    E. Velarde & J. Wong

  3. Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil

    A. S. Yamashita & E. T. Kimura

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  1. A. S. Yamashita
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Correspondence to G. J. Riggins.

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Yamashita, A.S., Baia, G.S., Ho, J.S.Y. et al. Preclinical evaluation of the combination of mTOR and proteasome inhibitors with radiotherapy in malignant peripheral nerve sheath tumors. J Neurooncol 118, 83–92 (2014). https://doi.org/10.1007/s11060-014-1422-5

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