HGG-02. DIANHYDROGALACTITOL (VAL-083) OVERCOMES MGMT- AND P53-MEDIATED CHEMO-RESISTANCE AND DISPLAYS SYNERGY WITH TOPOISOMERASE INHIBITORS
Bibliographic record
Abstract
The mortality rate of pediatric CNS cancer has not decreased as other pediatric cancers, and high-grade gliomas (HGG) are the main cause of death in children with brain tumors. Children with HGG have few therapeutic options and 5-year survival is less than 20%. Relapsed HGG have a uniformly fatal outcome despite all available treatments. The standard treatment for HGG is surgery followed by radiotherapy and temozolomide (TMZ) although the efficacy of TMZ in children is negligible. DNA repair protein O6-Methyl-Guanine-DNA-MethylTransferase (MGMT) is expressed in most pediatric HGG and expression is correlated with resistance to TMZ and nitrosoureas and dismal prognosis. VAL-083 is a bi-functional alkylating agent that readily crosses the blood-brain barrier and has demonstrated activity in pediatric brain tumors as well as a favorable safety profile in prior NCI-sponsored clinical trials. VAL-083 induces interstrand cross-links at guanine-N7 causing DNA double-strand breaks and cancer cell death. VAL-083 overcomes TMZ-resistance and is equally active against GBM cancer stem cells (CSCs) and non-CSCs independent of MGMT status, in vitro. We recently showed that VAL-083 leads to irreversible S/G2-phase cell cycle arrest and persistent activation of the homologous recombination DNA repair pathway. This mechanism-of-action of VAL-083 suggests the potential for synergy with topoisomerase inhibitors (TOPi), commonly used in the treatment of pediatric HGG, which require cancer cells to be in S-phase for optimal efficacy. Here, VAL-083 cytotoxicity and DNA damage-response was evaluated in SF188, Med8a, A549 and PC3 cell-lines. We report strong activity in p53-mutated Med8a and SF188 cells known to be radio- and chemo-resistant. Further, we report synergy between VAL-083 and both topoisomerase I and II inhibitors (camptothecin and etoposide) in both A549 and PC3 cell-lines. Our results support a distinct anti-cancer mechanism for VAL-083 compared to standard HGG chemotherapy, resulting in the ability to overcome chemo-resistance and exhibiting synergy with TOPi.
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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) | 0.001 | 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".