DRES-10. THE DISTINCT CYTOTOXIC MECHANISM OF DIANHYDROGALACTITOL (VAL-083) OVERCOMES CHEMORESISTANCE AND PROVIDES NEW OPPORTUNITIES FOR COMBINATION THERAPY IN THE TREATMENT OF GLIOBLASTOMA
Bibliographic record
Abstract
Treatment of glioblastoma (GBM) includes surgery and chemoradiation with temozolomide. Due to chemoresistance, nearly all tumors recur and 5-year survival is less than 3%. Various treatments, including anti-angiogenic treatment with bevacizumab, nitrosoureas and topoisomerase inhibitors, have failed to improve overall survival in recurrent GBM (rGBM). GBM tumors expressing O6-methylguanine-DNA-methyltransferase (MGMT) are resistant to temozolomide and nitrosourea, and deficient DNA mismatch repair (MMR) confers secondary resistance to temozolomide. Our recent phase I/II trial in rGBM patients previously treated with temozolomide and bevacizumab, suggested that VAL-083 may offer a clinically meaningful survival benefit for rGBM patients. VAL-083 is a first-in-class bi-functional DNA-targeting agent that readily crosses the blood-brain barrier and accumulates in brain tumor tissue. The mechanism-of-action of VAL-083 differs from other alkylating agents and overcomes both MGMT- and MMR-related resistance to temozolomide, in vitro. VAL-083 rapidly induces interstrand cross-links at N7-guanine, causing DNA double-strand breaks and persistent activation of the homologous recombination (HR) DNA repair pathway. Furthermore, VAL-083 potency is increased in HR-deficient cancer cells, suggesting increased cytotoxicity in HR-impaired tumors. Hypoxic GBM cells downregulate HR activity, thus proposing increased VAL-083 potency in hypoxic tumors. Bevacizumab increases intratumor hypoxia, suggesting VAL-083 as a treatment option in HR-deficient or hypoxic cancers following, or as part of combination with, bevacizumab. The potency of VAL-083 as part of a combinatory treatment with bevacizumab was investigated in GBM models under hypoxia both in vitro and in vivo. Separately, we demonstrated that VAL-083 induces irreversible S/G2-phase cell-cycle arrest, thus proposing synergy with S-phase specific chemotherapeutics, including topoisomerase and PARP inhibitors. Here, we investigated cytotoxicity of VAL-083 combinations with various topoisomerase and PARP inhibitors in a range of cancer cells. Our results support the potential of VAL-083 to i) overcome resistance to temozolomide, and ii) display synergy as part of combinatory therapies with topoisomerase or PARP inhibitors.
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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) | 0.003 | 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".