PDTM-46. TARGETING METABOLIC ADAPTATION IN MYC DRIVEN PEDIATRIC NEURONAL TUMORS
Bibliographic record
Abstract
MYC family proteins are implicated in many human cancers, but their therapeutic targeting has proven challenging. MYCN and c-MYC amplification in childhood neuroblastoma (NB) and medulloblastoma (MB) are associated with aggressive disease and high mortality. Novel and effective therapeutic strategies are therefore urgently needed for these tumors. MYC-driven oncogenic transformation impairs cell survival under nutrient deprivation (ND), a characteristic stress condition within the tumor microenvironment. We recently identified eukaryotic Elongation Factor 2 Kinase (eEF2K) as a pivotal mediator of the adaptive response of tumor cells to ND. We therefore hypothesized that eEF2K facilitates the adaptation of MYCN/MYC amplified NB/MB to ND, and that inhibiting this pathway can impair tumor progression. To test our hypothesis, we first analyzed publicly available genomic databases and tissue microarrays for eEF2K expression in NB and MB, and for links between eEF2K, MYCN/MYC, and clinical outcome. Effects of eEF2K inhibition were evaluated on survival of MYCN/MYC amplified versus non-amplified NB/MB cell lines under ND. Finally, NB xenograft mouse models were used to confirm in vitro observations. Our results indicate that high eEF2K expression and activity are strongly predictive of poor outcome in NB and MB (p<0.001), and correlate significantly with MYCN/MYC amplification (p<0.001). Inhibition of eEF2K significantly decreases survival of MYCN/MYC amplified NB/MB cell lines in vitro under ND. Knockdown of eEF2K under caloric restriction determines a twofold growth decrease of MYCN amplified NB xenografts. eEF2K represents a critical mediator for the adaptive response of MYCN/MYC amplified NB and MB to acute metabolic stress, and is therefore a promising therapeutic target. Future therapeutic studies will aim to combine eEF2K pharmacological inhibition with caloric restriction mimetics such as metformin or glycolysis inhibitors, as eEF2K activity appears to be critical under metabolic stress conditions.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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) | 0.001 | 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".