MODL-47. A NEW MOUSE MODEL OF IDH MUTATED GLIOMAS IDENTIFIES TUMOR CELLS OF ORIGIN AND DETERMINANTS OF SENSITIVITY TO IDH INHIBITORS
Bibliographic record
Abstract
Abstract Driver mutations in IDH1 and IDH2 characterize a substantial proportion of diffuse gliomas. These tumors are typically of lower grade at diagnosis, but many eventually transform to more aggressive disease. Furthermore, there is a lack of effective curative treatments. Mutated IDH molecules acquire neomorphic enzymatic activity, favoring the synthesis of D-2-hydroxyglutarate (D-2-HG). Accumulation of this metabolite perturbs many cellular functions and drives gliomagenesis through incompletely understood mechanisms. IDH mutations are early events in gliomagenesis, but the identity of the initiating cell type has been debated. Here, using genetically engineered mice, we found that combining Idh1R132H and Trp53 loss in oligodendrocyte progenitors leads to fully penetrant development of diffuse gliomas. The tumors recapitulate the cardinal features of the corresponding human disease. While heterogeneous, the mouse Idh1R132H and Idh1WT tumors show distinct patterns of transcriptional alterations and oncogenic copy number variants. Mutant IDH itself is an attractive drug target, as it is clonally expressed and usually retained during tumor evolution, even though its relevance for disease progression has been questioned. Nevertheless, recent clinical trials have demonstrated clear, but variable, anti-tumor effects of mutant IDH inhibitors in patients. To better understand the mechanistic basis for heterogeneous responses to mutant IDH inhibition, we performed CRISPR/Cas9 functional genomic screens in cell lines derived from the mouse Idh1R132H;Trp53MUT tumors. These revealed interactions between the mutant IDH inhibitor vorasidenib and molecules related to astrocytic differentiation, Notch signaling, and cell growth and metabolism. The translational relevance of these findings was supported by molecular data from human tumors, patients treated with IDH inhibitors, and human-derived cell models. Overall, these studies nominate oligodendrocyte progenitors as candidate cells of origin for IDH mutated gliomas, and point to strategies that may enhance the efficacy of IDH inhibitors.
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) | 0.001 | 0.001 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.002 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.001 | 0.000 |
| Research integrity | 0.001 | 0.003 |
| Insufficient payload (model declined to judge) | 0.004 | 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".