@article{7c96a85b00b74b6a9cc884d37e8dbad7,
title = "WNT activation by lithium abrogates TP53 mutation associated radiation resistance in medulloblastoma",
abstract = "TP53 mutations confer subgroup specific poor survival for children with medulloblastoma. We hypothesized that WNT activation which is associated with improved survival for such children abrogates TP53 related radioresistance and can be used to sensitize TP53 mutant tumors for radiation. We examined the subgroup-specific role of TP53 mutations in a cohort of 314 patients treated with radiation. TP53 wild-type or mutant human medulloblastoma cell-lines and normal neural stem cells were used to test radioresistance of TP53 mutations and the radiosensitizing effect of WNT activation on tumors and the developing brain. Children with WNT/TP53 mutant medulloblastoma had higher 5-year survival than those with SHH/TP53 mutant tumours (100% and 36.6% ± 8.7%, respectively (p < 0.001)). Introduction of TP53 mutation into medulloblastoma cells induced radioresistance (survival fractions at 2Gy (SF2) of 89% ± 2% vs. 57.4% ± 1.8% (p < 0.01)). In contrast, β-catenin mutation sensitized TP53 mutant cells to radiation (p < 0.05). Lithium, an activator of the WNT pathway, sensitized TP53 mutant medulloblastoma to radiation (SF2 of 43.5% ± 1.5% in lithium treated cells vs. 56.6 ± 3% (p < 0.01)) accompanied by increased number of γH2AX foci. Normal neural stem cells were protected from lithium induced radiation damage (SF2 of 33% ± 8% for lithium treated cells vs. 27% ± 3% for untreated controls (p = 0.05). Poor survival of patients with TP53 mutant medulloblastoma may be related to radiation resistance. Since constitutive activation of the WNT pathway by lithium sensitizes TP53 mutant medulloblastoma cells and protect normal neural stem cells from radiation, this oral drug may represent an attractive novel therapy for high-risk medulloblastomas.",
keywords = "2734, Adolescent, Cell Line, Tumor, Cell Survival, Cellular and Molecular Neuroscience, Cerebellar Neoplasms, Child, Child, Preschool, Cohort Studies, Female, Humans, International Cooperation, Lithium, Male, Medulloblastoma, Mutation, Neoplastic Stem Cells, Neurology (clinical), Radiotherapy, Tumor Suppressor Protein p53, Wnt Proteins, Wnt Signaling Pathway, Young Adult, beta Catenin, 2734, Adolescent, Cell Line, Tumor, Cell Survival, Cellular and Molecular Neuroscience, Cerebellar Neoplasms, Child, Child, Preschool, Cohort Studies, Female, Humans, International Cooperation, Lithium, Male, Medulloblastoma, Mutation, Neoplastic Stem Cells, Neurology (clinical), Radiotherapy, Tumor Suppressor Protein p53, Wnt Proteins, Wnt Signaling Pathway, Young Adult, beta Catenin",
author = "Luca Massimi and Marco Gessi and Nataliya Zhukova and Vijay Ramaswamy and Marc Remke and Martin, {Dianna C.} and Pedro Castelo-Branco and Zhang, {Cindy H.} and Michael Fraser and Ken Tse and Raymond Poon and Shih, {David J.H.} and Berivan Baskin and Ray, {Peter N.} and Eric Bouffet and Peter Dirks and {Von Bueren}, {Andre O} and Elke Pfaff and Andrey Korshunov and Jones, {David T.W.} and Northcott, {Paul A.} and Marcel Kool and Pugh, {Trevor J.} and Pomeroy, {Scott L.} and Yoon-Jae Cho and Torsten Pietsch and Stefan Rutkowski and Laszlo Bogn{\'a}r and Byung-Kyu Cho and Eberhart, {Charles G.} and Conter, {Cecile Faure} and Maryam Fouladi and French, {Pim J.} and Grajkowska, {Wieslawa A.} and Nalin Gupta and Peter Hauser and Nada Jabado and Alexandre Vasiljevic and Shin Jung and Seung-Ki Kim and Almos Klekner and Toshihiro Kumabe and Boleslaw Lach and Leonard, {Jeffrey R.} and Liau, {Linda M.} and Pollack, {Ian F.} and Ra, {Young Shin} and Rubin, {Joshua B.} and {Van Meir}, {Erwin G.} and Kyu-Chang Wang and Weiss, {William A} and Karel Zitterbart and Bristow, {Robert G.} and Benjamin Alman and Hawkins, {Cynthia E.} and David Malkin and Clifford, {Steven C.} and Pfister, {Stefan M.} and Taylor, {Michael D.} and Uri Tabori",
year = "2013",
doi = "10.1186/s40478-014-0174-y",
language = "English",
volume = "2",
pages = "174--186",
journal = "Acta neuropathologica communications",
issn = "2051-5960",
publisher = "London : BioMed Central",
}