Carbonic Anhydrase Inhibition Sensitizes Group 3 Medulloblastoma to Radiotherapy
Bibliographic record
Abstract
Group 3 (G3) medulloblastoma constitutes the most aggressive molecular subgroup, and nearly all patients present with metastases upon recurrence. Treatment for newly diagnosed medulloblastoma relies on a combination of maximal safe surgical resection, followed by chemotherapy and ionizing radiation, and no therapies have been shown to confer a survival benefit at the time of recurrence. Given the limited therapeutic options available for patients with medulloblastoma, especially at recurrence, and the incomplete understanding of the molecular mechanisms underlying resistance to treatment, we sought to uncover actionable targets and biomarkers that could help refine patient selection and treatment of newly diagnosed medulloblastoma to reduce the risk of recurrence. In clinically relevant mouse models of G3 medulloblastoma, CT-guided fractionated radiotherapy extended overall survival and induced the clonal selection of radioresistant subpopulations of tumor cells that drove medulloblastoma recurrence. Comparison of recurrent tumors with treatment-naïve newly diagnosed tumors revealed a gene expression signature that was found to be a biomarker of radioresistance and poor prognosis. This prognostic gene signature was shown to be subgroup specific in a large patient cohort. Recurrent tumors had elevated expression of carbonic anhydrase 4, and genetic and pharmacologic modulation of carbonic anhydrase 4 could promote or reduce resistance to radiotherapy. These data suggest that the FDA-approved carbonic anhydrase inhibitor acetazolamide may be a useful radiosensitizer to improve the efficacy of the treatment of newly diagnosed G3 medulloblastoma that could reduce the risk of tumor recurrence and improve survival in pediatric patients. SIGNIFICANCE: G3 medulloblastoma features a prognostic subgroup-specific gene expression signature and can be targeted with a carbonic anhydrase inhibitor to enhance radiosensitivity, reducing the risk of recurrence and improving survival.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.001 | 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 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".