P08.57 Distinct mechanism-of-action of dianhydrogalactitol (VAL-083) overcomes chemoresistance in glioblastoma
Bibliographic record
Abstract
Standard treatments for glioblastoma (GBM) include surgery, radiation and chemotherapy with temozolomide (TMZ). Nearly all tumors recur and 5-year survival is less than 3%, largely due to chemoresistance. Cancer cells utilize DNA damage repair pathways to overcome cytotoxicity of chemotherapy. GBM tumors expressing O6-methylguanine-DNA-methyltransferase (MGMT) are resistant to TMZ and nitrosourea, and deficient DNA mismatch repair (MMR) confers resistance to TMZ and platinum agents. Alterations in p53, particularly gain-of-function mutations, are correlated with increased MGMT and poor prognoses in GBM. Second line anti-angiogenic treatment with bevacizumab has been implicated in increased chemoresistance and has not improved overall survival. Thus, refractory GBM is a significant clinical challenge and novel therapeutic strategies to overcome chemoresistance are essential. VAL-083 is a bi-functional alkylating agent that readily crosses the blood-brain barrier and has shown activity against GBM in prior NCI-sponsored clinical trials. A Phase I/II clinical trial studying VAL-083 in recurrent GBM, after TMZ and bevacizumab failure, suggested the potential of VAL-083 to offer a clinically meaningful survival benefit. The mechanism-of-action of VAL-083 differs from other alkylating agents, including TMZ and nitrosoureas, inducing interstrand cross-links at guanine-N7 causing DNA double-strand breaks and cancer cell death. VAL-083 activity is independent of MGMT and p53 status and it is active against TMZ-resistant GBM cancer stem cells. Recent findings that VAL-083 leads to irreversible S/G2-phase cell cycle arrest, propose synergy with S-phase specific chemotherapeutics, including topoisomerase and PARP inhibitors. VAL-083 persistently activates the homologous recombination (HR) DNA repair pathway and its potency is increased in HR-impaired cancer cells, suggesting increased VAL-083 cytotoxicity in HR-impaired tumors. Further, hypoxic cancer cells downregulate HR, proposing increased VAL-083 potency in hypoxic tumors. Bevacizumab increases intratumor hypoxia, presumably impairing HR, proposing VAL-083 as a treatment option in HR-deficient or hypoxic cancers following, or as part of combination with, bevacizumab. Here, we investigated cytotoxicity and DNA damage response of VAL-083 combinations by crystal violet, western blot and flow cytometry in a range of cancer cells, and MMR-related chemoresistance using lentiviral MLH1 and MSH2 vectors. The potency of VAL-083 in GBM was investigated under hypoxia either in vitro or in vivo as part of a combination treatment with bevacizumab. Our results demonstrate a distinct anti-cancer mechanism for VAL-083, enabling i) ability to overcome resistance to TMZ, platinum agents, and nitrosoureas, ii) increased potency in cancers with impaired HR, and iii) synergy with topoisomerase and 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".