DDIS-11. MOLECULAR MECHANISMS OF DIANHYDROGALACTITOL (VAL-083) IN OVERCOMING CHEMO-RESISTANCE IN GLIOBLASTOMA
Bibliographic record
Abstract
Glioblastoma (GBM) is the most aggressive malignant brain cancer. The heterogeneous nature of GBM tumors and highly chemoresistant cancer stem-cells (CSCs) comprise significant clinical challenges. Most GBM tumors express O6-methylguanine-DNA-methyltransferase (MGMT) causing intrinsic chemoresistance to temozolomide and CCNU. Even tumors initially responsive to temozolomide, often recur with deficient DNA mismatch repair system (MMR) leading to acquired chemoresistance to temozolomide. Alteration in p53, particularly gain-of-function mutations, are correlated with poor prognoses in GBM, potentially by increasing MGMT-expression and temozolomide-resistance. Second-line treatment with bevacizumab, while successfully inducing intra-tumor hypoxia, has not improved overall survival. This is possibly due to GBM CSCs rapidly adapting to hypoxia by upregulating glucose-uptake and increasing invasiveness. Dianhydrogalactitol (VAL-083) is a bi-functional alkylating agent that readily crosses the blood-brain barrier, accumulates in brain tumor tissue and has demonstrated activity against GBM in prior NCI-sponsored clinical trials. VAL-083 induces interstrand cross-links at guanine-N7 causing DNA double-strand breaks and cell-death. VAL-083 is equally active against GBM CSCs and non-CSCs, and the activity is MGMT-independent and appears minimally dependent on wild-type p53, in vitro. A Phase I/II clinical trial studying VAL-083 in recurrent GBM, after temozolomide and bevacizumab failure, suggested potential of VAL-083 to offer clinically meaningful survival benefits. Here we report a distinct mechanism-of-action of VAL-083, showing that VAL-083 leads to irreversible S-phase cell-cycle arrest, activation of the homologous recombination pathway and ensuing cell-death, through mechanisms independent of MGMT and MMR. We used biochemical and microscopic analyses of DNA repair markers to investigate the VAL-083-induced DNA damage response in cancer-cells harbouring wild-type or mutated MMR-proteins and p53. We furthermore investigated the cytotoxic activity of VAL-083 against GBM cancer-cells under normoxia vs. hypoxia. Our results demonstrate a distinct anti-cancer mechanism for VAL-083. At the meeting we will present further results clarifying VAL-083’s potential to overcome chemoresistance in the treatment of GBM.
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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) | 0.001 | 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".