MEDU-47. PEROXIREDOXIN1 IS A THERAPEUTIC TARGET IN GROUP-3 MEDULLOBLASTOMAS
Bibliographic record
Abstract
Group-3 Medulloblastomas (MBL) has the worst prognosis due to its resistance to radiation and chemotherapy with a 5-year survival of 30%. Thus, there is an urgent need to elucidate targets that can sensitize Group-3 tumors to conventional treatments. We identified PRDX1 as a candidate therapeutic target for therapy sensitization in group-3 tumors. PRDX1 catalyzes the conversion of hydrogen peroxide to water and oxygen. We hypothesized that inhibiting PRDX1 would lead to oxidative stress and increase susceptibility to ionizing radiation via extensive DNA damage. Accordingly, when PRDX1 was targeted using Adenanthin (specific chemical inhibitor) or RNAi, Group-3 MBL (D425-MED) cells were rendered hypersensitive to radiation. Mechanistically, targeting PRDX1 resulted in an increase in reactive oxygen species, extensive oxidative DNA damage and an induction of the apoptotic pathway. Similarly, overexpression of PRDX1 in MBL cells susceptible to radiation (DAOY, UW-228) resulted in radiation resistance. However targeting PRDX1 in normal astrocytes did not have any sensitization effects. The in-vitro results were validated in-vivo using flank tumors (Adenanthin) and an orthotopic murine model (both RNAi and Adenanthin) using Group-3 MBL cells (D425-MED) and patient derived xenografts (MB3W1). Briefly, mice bearing Group-3 MBL tumors (D425-MED / MB3W1) when subjected to treatment with Adenanthin combined with radiation achieved a synergistic increase in survival. To fully evaluate the therapeutic potential of PRDX1 across all groups of MBL, we determined the expression of PRDX1 in a validated MBL tumor micro-array (TMA) by immunohistochemistry and correlated it with patient characteristics, therapeutic response and clinical outcomes. We also evaluated the role of PRDX1 in Group-3 MBL stem cells with respect to radiation resistance, invasion and migration. The results from these experiments will be presented in the meeting. Our data suggest that PRDX1 is a therapeutic target in Group-3 MBL and Adenanthin as a small molecule inhibitor of PRDX1.
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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) | 0.002 | 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".