EXTH-93. Combination of ALK2 and cholesterol targeting agents exploits linked genetic and metabolic dependencies in diffuse midline glioma
Bibliographic record
Abstract
Abstract The discovery that ACVR1-mutations arise in ~25% of DMG H3K27-altered patients has led assessment of both the dependency of ACVR1-mutant cells on ALK2 and the effectiveness of ALK2 inhibitors (ALK2i), however as single-agents these are yet to translate into the clinic. Here, we perform high-throughput screens to identify therapeutic ALK2i combination partners and characterise pre-clinical ALK2 inhibitors of different chemotypes using a multi-omic approach. Combinatorial CRISPR screens identified multiple ALK2i sensitising hit genes which encode for key enzymes in the cholesterol synthesis pathway (EBP/DHCR24/LSS). Drug-combination screens identified clinically well-tolerated statins, including simvastatin/lovastatin which target the rate-limiting cholesterol synthesis enzyme HMG-CoA reductase, and estrogen receptor inhibitors, including Tamoxifen, which exhibits off-target effects on EBP, as sensitisers to ALK2i. Global transcriptomics, proteomics and metabolomics revealed a novel link between ALK2 signalling and cholesterol homeostasis, with ALK2i treatment significantly decreasing the expression cholesterol biosynthesis genes/proteins (SREBF2/HMGCR/EBP) while increasing those associated with cholesterol transport (ABCA1/MYLIP). Metabolomic analysis confirmed these changes were associated with a significant decrease in cholesterol and an increase in the precursor desmosterol. Validation of screening hits revealed strong synergy between ALK2i and cholesterol biosynthesis inhibitors targeting different nodes of the pathway. This was also observed in vivo, the combination treatment significantly increased the median survival compared to vehicle but not to single-agents. Forced differentiation of DMG cells to an astrocyte-like cell state increased cholesterol production and led to a significant decrease in M4K2009 sensitivity and synergy with statins, which was phenocopied when DMG cells were co-cultured with normal astrocytes. This was overcome in vitro, ex vivo and in vivo using a triple combination including a LXR agonist (LXR623) to promote cholesterol export. We identify a previously unappreciated link between ALK2 signalling and cholesterol homeostasis which may be exploited clinically by combining ALK2i with routinely-used statins and BBB-penetrant LXR agonists.
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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 | 0.001 |
| 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".