MBRS-52. TARGETING PRUNE-1 IN A GEMM OF METASTATIC MEDULLOBLASTOMA: A POTENTIAL ROUTE OF INHIBITION FOR NEW FUTURE THERAPIES
Bibliographic record
Abstract
Genetic modifications during development of paediatric Group3 Medulloblastoma (MBGroup3) are responsible for its highly metastatic properties and poor patient survival rates. We found PRUNE-1 to be highly expressed in metastatic MBGroup3, which is characterised by TGF-β signalling activation and OTX2 expression. The molecular mechanism was identified underlying the metastatic dissemination of those PRUNE-1-driven-MBGroup3. PRUNE-1, through its binding to NDPK-A (NME-1), enhances the canonical TGF-β pathway activation, upregulates OTX2 and SNAIL, and inhibits PTEN. We also identified a new non-toxic small molecule pyrimido-pyrimidine derivative (AA7.1) with the ability to enhance PRUNE-1 degradation and to impair tumour progression and metastases in vivo using orthotopic xenograft models with metastatic MBGroup3 cells. Using whole exome sequencing technology in primary human metastatic MB cells, we also defined new deleterious ‘non-synonymous homozygous’ gene variants with effects on immune cells activation/differentiation, as part of a protein network of relevance for metastatic processes (Ferrucci et al., Brain In Press, 2018). We developed a Genetically Engineered Mouse Model (GEMM) of PRUNE-1-driven-metastatic MB. This GEMM (MATH1-PRUNE-1/Cyclin-B2-LUC) was generated by overexpressing PRUNE-1 in the developing cerebellum (using MATH1 promoter) together with the Luciferase gene (under the control of Cyclin-B2 promoter) in a background TP53-/-, thus generating Medulloblastoma. Chemotherapeutic drugs for high-risk MB together with AA7.1 were tested in combination on medullospheres showing an impairment of cell index proliferation. In vivo, in xenografted studies, we showed tumour inhibition at both the primary and metastatic sites together with immunonomodulatory effects. Altogether these results are of importance for future targeted therapies of high risk metastatic MBGroup3.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| 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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.000 | 0.000 |
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 teacher head, 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".