Abstract A038: Lomitapide enhances cytotoxic effects of temozolomide in chemo-resistant glioblastoma
Bibliographic record
Abstract
Abstract Glioblastoma is the most prevalent and aggressive malignant primary brain tumour in adults, with a median survival following multi-modality therapy of 14.6 months. The current standard of care for patients with glioblastoma includes maximal safe surgical resection followed by radiation and chemotherapy with the alkylating agent, temozolomide. However, more than one-third of patients experience tumour progression during conventional therapy, suggesting that many of these patients harbor tumour cells that are intrinsically resistant to temozolomide-associated cytotoxicity. There is significant need for novel therapies to complement or improve our current treatments. Drug repurposing has gained attention in cancer research for its time- and monetary-efficiency in advancing chemical leads for clinical studies. The use of FDA-approved agents significantly decreases the time required for agents to go from bench to bedside, as toxicological data for these drugs is publicly available. In this study, we performed a high-throughput drug screen using a library of approximately 900 FDA-approved candidates. We identified eight agents that were predicted to have good brain penetration and exhibited cytotoxicity against glioma cells when combined with TMZ. As multiple recent reports have identified cholesterol biosynthesis as a vulnerability in glioblastoma, we chose to investigate the lipid-lowering drug (statin), lomitapide (Juxtapid). We find that lomitapide inhibits the mevalonate pathway of de novo cholesterol biosynthesis in TMZ-resistant glioma cells, resulting in cholesterol and ubiquinone (CoQ10) deficiency. Depletion of antioxidant CoQ10 in turn causes excessive accumulation of cellular reactive oxygen species that prime TMZ-resistant glioma cells for ferroptosis. In a mouse xenograft model, concurrent treatment with lomitapide and TMZ significantly delays tumour recurrence and prolongs survival, compared to TMZ alone. Our findings identify lomitapide as a potential therapeutic agent capable of targeting treatment resistance and delaying tumour progression in glioblastoma. Citation Format: Alyona Ivanova, Taylor M. Wilson, Kimia Ghannad-Zadeh, Esmond Tse, Robert Flick, Megan Wu, Sunit Das. Lomitapide enhances cytotoxic effects of temozolomide in chemo-resistant glioblastoma [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A038.
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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) | 0.001 | 0.000 |
| Bibliometrics | 0.001 | 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) | 0.002 | 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".