Recent discoveries enabled us to divide medulloblastoma into molecular sub-groups and uncover novel mutations in these tumors. However, except for superior survival of the WNT sub-group, the prognostic and therapeutic implications of these observations remain unclear. TP53 mutations which confer radioresistance revealed conflicting clinical relevance in different studies.
We hypothesized that the effect of TP53 mutations on survival is modulated through molecular sub-grouping. This is especially important since therapeutic targeting of WNT can be achieved with administration of lithium.
Here we first confirmed that TP53 mutant tumors confers unfavorable outcome only in SHH subgroup, but not in WNT. We demonstrated that while TP53 mutations cause radioresistance, activation of WNT/β-catenin signaling radiosensitizes medulloblastoma cells. We demonstrated that lithium activates the WNT pathway and effectively sensitize medulloblastoma cells to radiation. Furthermore, lithium did not sensitize normal neural stem cells to radiation, suggesting its potential as an effective radiosensitizer for medulloblastoma.
| Identifer | oai:union.ndltd.org:TORONTO/oai:tspace.library.utoronto.ca:1807/33626 |
| Date | 27 November 2012 |
| Creators | Zhukova, Nataliya |
| Contributors | Tabori, Uri |
| Source Sets | University of Toronto |
| Language | en_ca |
| Detected Language | English |
| Type | Thesis |
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