Abstract 1369: Dianhydrogalactitol (VAL-083) synergizes with topoisomerase inhibitors to overcome homologous recombination repair activity in glioblastoma and prostate cancer cells
Bibliographic record
Abstract
Abstract Dianhydrogalactitol (VAL-083) is a bi-functional DNA-damaging agent that targets N7-guanines and causes DNA inter-strand crosslinks. VAL-083 is a small water-soluble molecule that readily crosses blood-brain-barrier and accumulates in brain tumor tissue, making it a good candidate for targeting brain malignancies, such as glioblastoma multiforme (GBM). VAL-083 has demonstrated anti-tumor activity in prior NCI-sponsored clinical trials in brain tumors and other cancer types. Previous research in our group demonstrates VAL-083-induced DNA inter-strand crosslinks lead to replication-dependent DNA double strand break (DSB) lesions that are preferentially repaired by homologous recombination (HR) in non-small cell lung cancer (NSCLC) cells. To investigate if the observed effects of VAL-083 in NSCLC cells translate to other cancer indications as well, we tested the cytotoxic activity of VAL-083 in a panel of GBM and prostate cancer cell lines. Crystal violet cell proliferation assay showed broad cytotoxicity of VAL-083 in low concentration (µM) range in all the cell lines tested. Immunofluorescent and propidium iodide staining followed by flow cytometric analysis furthermore showed that VAL-083 treatment induced replication-dependent S/G2 cell cycle arrest. DNA repair markers were investigated by western blot and confocal microscopy analyses and confirmed the activation of HR DNA repair pathway after VAL-083 treatment in cancer cells. Using lentiviral transduction of MLH1 and MSH2 expression vectors in HCT116 and LoVo cell lines, we investigated if VAL-083 activity was affected by DNA mismatch repair (MMR), which is the secondary temozolomide (TMZ)-resistance mechanism in GBM patients. Our data showed that VAL-083 cytotoxicity was independent of MMR, suggesting that VAL-083 is able to overcome MMR-mediated TMZ-resistance in GBM patients. Additionally, we demonstrated synergistic effects between VAL-083 and inhibitors of both topoisomerase I and II (camptothecin, irinotecan and etoposide) in GBM and prostate cancer cells. Taken together. our present study validated the broad cytotoxic effect and mechanism-of-action of VAL-083 in a variety of cancer cells and suggested that VAL-083 is able to overcome MMR-mediated TMZ resistance in GBM. We further demonstrated synergy between VAL-083 and topoisomerase inhibitors in GBM, prostate cancer and NSCLC cell lines. This provides good guidance for improved treatment strategies to use VAL-083 either as single agents or as part of combination regimens in the treatment of cancer patients. Citation Format: Beibei Zhai, Sudha Sravanti Kotapalli, Jeffrey A. Bacha, Dennis M. Brown, Anne Steino, Mads Daugaard. Dianhydrogalactitol (VAL-083) synergizes with topoisomerase inhibitors to overcome homologous recombination repair activity in glioblastoma and prostate cancer cells [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1369.
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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) | 0.002 | 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".