LGG-60. Development and implementation of a complementary diagnostic tool to detect targetable pathways in pediatric glioma patients
Bibliographic record
Abstract
Abstract Pediatric Low grade gliomas are mainly driven by MAPK alterations including mutations in BRAF (BRAF fusions and BRAFV600) and FGFR. This has led to the study of BRAF, MEK and more recently FGFR inhibitors resulting in variable responses. We hypothesize that differing levels of RAS_MAPK coupled with alternate pathway activation may be driving this variability. To address this, we designed a custom NanoString assay that integrates proteomic and transcriptomic profiling of 4 key cancer-related, actionable pathways (MAPK, PI3K-AKT-mTOR, JAK-STAT, and NFkB) with robust results on formalin-fixed paraffin embedded tissue, including archival samples up to approximately 15 years old. We validated this assay using 15 gold standard cell lines with defined changes in each pathway including both isogenic activating mutations and perturbation with inhibitors. These findings were confirmed using data from the Cancer Cell Line Encyclopedia. The panel was further validated using a cohort of 40 low grade glioma samples with available RNAseq data where the RNA expression signatures had high concordance between assays. We have currently run the assay on over 200 surgical tumor samples, including 206 gliomas, 15 ependymomas, 11 medulloblastomas, 14 high grade gliomas and 10 control normal brain specimens. Findings indicate significant variability in pathway activations between tumors, although PLGG overall have higher MAPK activation scores than control tissue and other tumor types, a subset of these tumors have increased activity in PIK , JAK and NFKB pathways, underscoring the importance of integrating transcriptomic and proteomic information in precision oncology treatments. Finally, single cell RNA sequencing data from pilocytic astrocytomas demonstrates significant heterogeneity in pathway activation states within the tumor cells, as well as high pathway activations in some tumor associated microglia. This raises further research questions regarding the role of tumor heterogeneity in treatment failures and the impact of targeted therapies on the tumor immune microenvironment.
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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 | 0.001 | 0.001 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.000 |
| Scholarly communication | 0.001 | 0.000 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.002 | 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".