P08.47 Dianhydrogalactitol (VAL-083) causes bifunctional alkylation leading to irreparable DNA double-strand breaks, S/G2 phase cell-cycle arrest and tumor cell death in an MGMT independent manner offering a unique treatment paradigm for GBM
Bibliographic record
Abstract
Glioblastoma (GBM) is the most common brain cancer. Systemic therapy with temozolomide or nitrosoureas is often ineffective due to the activity of the DNA repair enzyme O6-methylguanine-DNA-methyltransferase (MGMT). Patients with recurrent GBM have limited treatment options and very poor prognosis. Dianhydrogalactitol (VAL-083) is a first-in-class bifunctional alkylating agent that rapidly induces interstrand DNA cross-links targeting N7 of guanine leading to cell cycle arrest and apoptosis due to DNA double-strand breaks. VAL-083 readily crosses the blood-brain barrier, accumulates in brain tumor tissue and has shown activity in prior NCI-sponsored clinical trials against CNS tumors, including GBM and medulloblastoma. We have previously shown that VAL-083´s cytotoxic activity is independent of MGMT in contrast to temozolomide and nitrosoureas. We have also demonstrated VAL-083 is active against GBM cancer stem cells (CSCs) and acts as a radiosensitizer in GBM CSCs, in vitro. We have also previously shown that VAL-083 circumvents cisplatin-resistance and is less dependent on p53 activity than cisplatin suggesting a distinct mechanism of action for VAL-083. We recently completed enrollment of a Phase I/II clinical trial in the United States for recurrent GBM in patients who have failed temozolomide and bevacizumab (clinicaltrials.gov identifier: NCT01478178). Separate clinical trials are planned in GBM patients with high expression of MGMT both in recurrent bevacizumab-naive GBM patients (clinicaltrials.gov identifier: NCT02717962) and in newly diagnosed GBM patients utilizing MGMT promoter methylation as a validated biomarker for patient selection. Here we report new insights into VAL-083 mechanism of action by showing that VAL-083 rapidly induces interstrand DNA cross-links leading to irreversible S/G2 cell-cycle arrest and cell death caused by replication-dependent DNA damage. VAL-083 pulse-treatment leads to persistent phosphorylation of DNA double-strand break (DSB) sensors ATM, single-strand DNA-binding Replication Protein A (RPA32), and histone variant H2A.X. After 10 months in culture, following a standard protocol for inducing chemo-resistance, cancer cells remained sensitive to VAL-083 at low M concentrations. Taken together, these results support a unique molecular mechanism for VAL-083 that differs from both temozolomide, nitrosoureas or cisplatin. Our data further suggest that the mechanism of VAL-083 is impervious to important DNA-repair strategies employed by cancer cells to escape effects of alkylating agents commonly used in the treatment of GBM and that efficient resistance mechanisms against VAL-083 treatment are not easily acquired by cancer cells.
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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 | 0.000 |
| Insufficient payload (model declined to judge) | 0.002 | 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".