DRES-10. TEMOZOLOMIDE-ASSOCIATED HYPERMUTATION DETECTED WITH A GENE PANEL SIGNATURE IMPROVES IMMUNE RESPONSE IN GLIOBLASTOMA
Bibliographic record
Abstract
Abstract Glioblastoma (GBM) is the most common and deadly type of malignant brain cancer in adults. While current standard of care which combines resection, radiation therapy (RT) and Temozolomide (TMZ) effectively eliminates primary disease, recurrence is inevitable, occurs rapidly following treatment and is ultimately lethal due to limited therapeutic opportunities of recurrent GBM. Hypermutation has been reported to occur in a subset of both low and high-grade gliomas and emerges after exposure to TMZ. Mutational inactivation and loss of mismatch repair (MMR) gene expression lead to the accumulation of single nucleotide polymorphisms throughout the genome. To date, the gain of hypermutation and subsequent therapeutic responses are still largely unknown. We hypothesized that hypermutant (HM) and non-hypermutant (NH) tumors represent two recurrent GBM subtypes, which has distinct therapeutic vulnerabilities. In addition, given the lack of concordance between microsatellite instability (MSI) and occurrence of hypermutation in GBM, we sought to derive a limited gene panel which can be used as surrogate biomarker for hypermutation following TMZ to replace whole exome sequencing (WES). Using public datasets, we demonstrated that recurrent GBM can be clustered into two subtypes: HM and NH. We used matched primary and recurrent GBM datasets to derive a gene panel signature, which is uniquely mutated at recurrence in HM GBM and confirmed the specificity of this panel in an independent dataset. Furthermore, we utilized patient derived xenograft (PDX) models to generate pre-clinical models and demonstrated that HM recurrent GBM are more immune responsive while NH recurrent GBM maintained sensitivity to a range of alternate chemotherapies such as cisplatin and RT. Finally, we demonstrated that this signature is represented in exosomes and can be enriched by use of tumor specific antibody capture methods to improve the sensitivity of hypermutation detection in liquid biopsy.
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 | 0.000 |
| 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".