title: mTOR pathway as a potential target in a subset of human medulloblastoma.
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.
authors.affiliation: 2nd Department of Pediatrics, Semmelweis University, Tűzoltó utca 7-9, H-1094, Budapest, Hungary.
authors.forename: Tímea
authors.initials: T
authors.lastname: Pócza
authors.forename: Anna
authors.initials: A
authors.lastname: Sebestyén
authors.forename: Eszter
authors.initials: E
authors.lastname: Turányi
authors.forename: Tibor
authors.initials: T
authors.lastname: Krenács
authors.forename: Agnes
authors.initials: A
authors.lastname: Márk
authors.forename: Tamás Béla
authors.initials: TB
authors.lastname: Sticz
authors.forename: Zsuzsanna
authors.initials: Z
authors.lastname: Jakab
authors.forename: Péter
authors.initials: P
authors.lastname: Hauser
mesh_terms: D000293:Adolescent; D000328:Adult; D014408:Biomarkers, Tumor / Q000378:metabolism*; D049109:Cell Proliferation / Q000187:drug effects; D002528:Cerebellar Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007124:Immunoenzyme Techniques; D007223:Infant; D008297:Male; D000076222:Mechanistic Target of Rapamycin Complex 1; D008527:Medulloblastoma / Q000188:drug therapy / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D046912:Multiprotein Complexes / Q000037:antagonists & inhibitors / Q000378:metabolism*; D009367:Neoplasm Staging; D010766:Phosphorylation / Q000187:drug effects; D011379:Prognosis; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D015398:Signal Transduction / Q000187:drug effects; D015996:Survival Rate; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D046888:Tissue Array Analysis; D014407:Tumor Cells, Cultured; D055815:Young Adult
chemical_list: D014408:Biomarkers, Tumor; D046912:Multiprotein Complexes; D047428:Protein Kinase Inhibitors; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
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