EXTH-36. SHIFTING FROM EPIGENETICS TO THE EPICHAPEROME: HSP90 AS A THERAPEUTIC TARGET FOR H3K27M DIFFUSE MIDLINE GLIOMA (DMG)
Bibliographic record
Abstract
Abstract Diffuse midline gliomas (DMG) are lethal pediatric brain tumours, the majority of which have truncal histone (H3K27M) mutations. To investigate cellular vulnerabilities of histone mutant cells we generated oligodendrocyte precursor cells (OPC) isogenic cell lines and performed a high-throughput synthetic lethality drug screen (2400 small molecules). This identified HSP90 inhibitors as a potential therapeutic option for H3K27M DMG. We hypothesize that epichaperome HSP90 inhibitors present a new therapeutic approach targeting multiple aspects of DMG oncogenicity. HSP90 inhibitors, PU-H71 and PU-HZ151, effectively reduced viability of DMG lines in vitro in the low nanomolar range and result in caspase mediated cell death (p<0.0001 1 uM, p<0.05 500 nM, n=6). PU-HZ151 treated mice had a survival benefit vs control mice injected with orthotopic DMG xenografts (p=0.0012). In diseased cells, activated HSP90 forms a scaffold defined as the epichaperome. To unravel the molecular mechanisms of epichaperome inhibition in DMG cells, we performed epichaperomics – a pull down of epichaperome HSP90 with co-chaperones and clients followed by LC-MS/MS analysis. We identified an interactome enriched with proteins involved in cell cycling, RAS/MAPK signaling, immune response, and metabolic reprogramming. Proteomic and phosphoproteomic profiling of DMG cells post-PU-HZ151 treatment provided insights into the direct downstream effects critical for maintaining DMG viability, identified functional vulnerabilities primed by epichaperome inhibition including downregulation of cell cycling, and upregulation of HSF1 mediated cellular response to stress. In silico screening and kinase enrichment analysis highlighted CSNK2A1 as a top active kinase in DMG cells following PU-HZ151 treatment. To enhance the therapeutic efficacy of epichaperome inhibition, we employed the CSNK2A1 kinase inhibitor, CX-4945, in combination with PU-HZ151, resulting in the effective ablation of DMG patient cells in vitro. These data highlight the potential of epichaperome inhibitors for DMG treatment, as they target multiple DMG oncogenic pathways.
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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 | 0.000 |
| 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".