Abstract LB-210: Abrogation of mutant <i>TP53</i> radiation resistance by lithium induced <i>CTNNB1</i> (β-catenin) activation in medulloblastoma.
Bibliographic record
Abstract
Abstract Introduction: Medulloblastoma (MB) is the most common paediatric malignant brain neoplasm. 30 % of patients will reccur and die of their tumour. TP53 mutations confer radiation resistance; we have recently demonstrated that somatic mutations in TP53 are predictive of poor survival in patients with MB. Patients with both TP53 and WNT activating CTNNB1 (β-catenin) mutations demonstrate improved survival compared to patients with TP53 mutations alone. WNT pathway is abrogated in 10% of MB. Lithium Chloride (LiCl) treatment constitutively activates WNT pathway by inhibition of Gsk3β-mediated degradation of β-catenin. Radiation therapy is key treatment in MB; hence we hypothesized that activation of WNT/β-catenin signalling can rescue radiation resistance of TP53 mutant phenotype, sensitize MB cells to radiation and can be achieved with administration of LiCl. Methods: Human MB, TP53 wild type (wt) and mutant (mut), all CTNNB1 wt cell lines were used to investigate radiation response and effect of LiCl on cell survival by clonogenic assays. Functional roles of TP53 and CTNNB1 mutations in response to LiCl/radiation treatments were assessed by transfection of mutant genes on a wild type background. Double strand (DS) DNA damage-repair was assessed by γH2AX immunofluorescence (IF). Normal neuronal stem cells were used to assess effects of LiCl/radiation on normal brain tissue by clonogenic assay. Results: TP53 mut MB cells were resistant to radiation compared to TP53 wt cells by clonogenic assay (p<0.01), accompanied by more efficient DNA damage response manifested by lower numbers of γH2AX foci. Transfection of R175H dominant-negative TP53 mutation to wt cells resulted in increased clonogenic potential post-radiation (p<0.01). MB cells transfected with CTNNB1 S33Y mutation revealed increased radiosenstivity especially in TP53 mut MB (p<0.01). LiCl treatment resulted in nuclear translocation of β-catenin and signalling activation by luciferase assay, which is consistent with activation of WNT pathway. Treatment with LiCl increased radiation sensitivity of both wt and mut TP53 cells (p<0.01; p<0.05 respectively), accompanied by increased DS DNA damage and delayed repair in both lines by γH2AX IF. LiCl treatment of normal neuronal stem cells did not sensitize them to radiation suggesting that LiCl is a tumour specific treatment. Conclusions: Constitutive activation of β-catenin by LiCl sensitizes TP53 mut MB cells to radiation possibly through activation of β-catenin/TCF mediated transcription and impaired DS DNA repair response. These findings may explain survival advantage in CTNNB1 mut MB patients harbouring TP53 mutation. Knowing safety of LiCl and its neuroprotective capacity in normal neuronal cells, oral administration of LiCl may represent an attractive novel therapy for MB patients. Investigations of the molecular mechanisms governing this phenomenon are ongoing. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr LB-210. doi:1538-7445.AM2012-LB-210
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.000 | 0.000 |
| Meta-epidemiology (narrow) | 0.000 | 0.000 |
| Meta-epidemiology (broad) | 0.000 | 0.000 |
| Bibliometrics | 0.000 | 0.000 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.000 | 0.000 |
| Open science | 0.000 | 0.000 |
| Research integrity | 0.000 | 0.001 |
| Insufficient payload (model declined to judge) | 0.003 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".