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mTOR Pathway As a Potential Target In a Subset of Human Medulloblastoma

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Pathology & Oncology Research

Abstract

As mammalian Target of Rapamycin (mTOR) plays role in protein synthesis and metabolism, mTOR pathway activation is involved in the pathogenesis of several types of tumors. Our aim was to elucidate its role in medulloblastoma in terms of prognosis and as a therapeutic target. Members of activated mTOR complex 1 (mTORC1) pathway, phospho-mTOR (p-mTOR) and phospho-S6 (p-S6) were examined by immunohistochemistry in formalin fixed paraffin embedded samples of 40 patients with medulloblastoma, and results were compared to clinical features and survival of patients. In proliferation assays, Daoy and UW228–2 medulloblastoma cell lines were tested by rapamycin, an mTORC1 inhibitor, and NVP-BEZ235, a dual mTOR and phosphatidylinositol 3-kinase (PI3K) inhibitor, each in monotherapy and in combination with cytostatic drugs (cisplatin, etoposide). Components of mTORC1 and mTORC2 complexes were also examined in these cell lines. Neither presence of p-mTOR (32.5 %) nor p-S6 (32.5 %) correlated with age, gender or histological subtype. In 22.5 % of cases simultaneous expression of p-mTOR and p-S6 was shown. Kaplan-Meier analysis showed inferior survival of patients expressing both marker proteins, but it was not statistically significant, probably due to low case number. UW228–2 cells had greater sensitivity to mTOR inhibitors, possibly due to its higher mTORC1 specific protein expression levels, compared to Daoy cells. In both cell lines antiproliferative effect of cytostatic drugs was significantly enhanced by mTOR inhibitors (p < 0.05). Based on our in vitro and clinicopathological studies mTOR inhibitors may have a role in the future treatment of a subset of patients with medulloblastoma.

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Acknowledgments

We thank Mária Csorba, Edit Parsch, Zsuzsanna Kaminszky and Renáta Kiss for excellent technical assistance and Dr. J. Silber (University of Washington, Seattle, WA, USA) for providing UW228–2 medulloblastoma cell line.

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. 2nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, H-1094, Budapest, Hungary

    Tímea Pócza, Zsuzsanna Jakab & Péter Hauser

  2. Department of Molecular Genetics, National Institute of Oncology, Ráth Gy. u 7-9, H-1122, Budapest, Hungary

    Tímea Pócza

  3. 1st Department of Pathology and Experimental Cancer Research, Semmelweis University, Üllői út 26, H-1085, Budapest, Hungary

    Anna Sebestyén, Eszter Turányi, Tibor Krenács, Ágnes Márk & Tamás Béla Sticz

  4. Tumor Progression Research Group, Joint Research Organization of the Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary

    Anna Sebestyén

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  1. Tímea Pócza
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Pócza, T., Sebestyén, A., Turányi, E. et al. mTOR Pathway As a Potential Target In a Subset of Human Medulloblastoma. Pathol. Oncol. Res. 20, 893–900 (2014). https://doi.org/10.1007/s12253-014-9771-0

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  • DOI: https://doi.org/10.1007/s12253-014-9771-0

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