PDTM-27. DIANHYDROGALACTITOL (VAL-083) OVERCOMES CHEMORESISTANCE IN PEDIATRIC MALIGNANT BRAIN TUMORS AND DISPLAYS SYNERGY WITH TOPOISOMERASE INHIBITORS
Bibliographic record
Abstract
More children die from brain cancer than from any other disease. Medulloblastoma (MB) and pediatric high-grade gliomas (pHGG) are the most common malignant brain cancers in children. Children with pHGG have few therapeutic options and 5-year survival is less than 20%. Treatment includes surgery, radiotherapy and various chemotherapeutic combinations often including topoisomerase inhibitors and/or temozolomide (TMZ). The expression of the DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT) is strongly correlated with TMZ-resistance and is highly expressed in many pHGG, and deficient DNA mismatch repair (MMR) (25% of pHGG) confers a secondary mechanism of TMZ-resistance. VAL-083 is a novel bi-functional DNA targeting agent that readily crosses the blood-brain barrier and accumulates in brain tumor tissue. In prior NCI-sponsored clinical trials, VAL-083 was well-tolerated and demonstrated activity against pediatric brain tumors, including pHGG and MB. VAL-083 induces interstrand cross-links at N7-guanine, DNA double-strand breaks and irreversible S/G2-phase cell cycle arrest leading to persistent activation of the homologous recombination (HR) DNA repair pathway and cancer cell death. VAL-083 overcomes MGMT-related resistance mechanisms and is equally active against HGG cancer stem cells and non-stem cells, in vitro. Here, we report strong VAL-083 activity against pHGG (SF188), MB (Med8a) and adult HGG (T98G) cancer cells known to be radio- and chemoresistant, independent of p53 and MGMT status. Further, VAL-083 cytotoxicity was shown to be MMR-independent in two colorectal cancer cell lines. We also report strong synergy between VAL-083 and inhibitors of both topoisomerase I and II (camptothecin and etoposide) in A549 and PC3 cancer cell lines. Our results suggest a distinct anti-cancer mechanism for VAL-083 compared to standard MB/pHGG chemotherapy, resulting in the ability to overcome MGMT- and MMR-related chemoresistance and exhibiting synergy with topoisomerase 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) | 0.001 | 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".