Abstract B30: Dianhydrogalactitol (VAL-083) has the potential to overcome major challenges in the treatment of DIPG
Bibliographic record
Abstract
Abstract Despite several decades of clinical trial, diffuse intrinsic pontine gliomas (DIPG) continue to have a dismal outcome and survival remains dismal. DIPG is inoperable and standard treatment is radiation alone, as the addition of chemotherapy has not improved survival. Major obstacles to the successful treatment of DIPG include an intact blood-brain barrier impeding drug penetration and inherent tumor-cell resistance mechanisms to chemotherapeutics. Dianhydrogalactitol (VAL-083) is a structurally unique bifunctional DNA targeting agent that readily crosses the blood-brain barrier. VAL-083 forms interstrand DNA crosslinks at the N7 position of guanine, leading to persistent and irreversible DNA double-strand breaks, cell cycle arrest, and ultimately cancer cell death. VAL-083 has cytotoxic activity in several pediatric brain tumors as assessed in historical NCI-sponsored clinical trials, both as a single agent and in combination with other chemotherapeutics. We have previously demonstrated that VAL-083 is able to overcome chemoresistance mediated by DNA repair protein O6-methylguanine DNA methyltransferase (MGMT). Expression of MGMT is strongly correlated with resistance to temozolomide (TMZ), which is commonly used in combination with radiation for the treatment of adult brain tumors. VAL-083 activity is also independent of DNA mismatch repair (MMR) system in vitro, a secondary mechanism of resistance to TMZ. VAL-083 potentiates the effect of radiation in TMZ-resistant adult glioblastoma (GBM) cells in vitro and overcomes TMZ resistance in GBM cancer stem cells (CSCs) and non-CSCs. Additionally, VAL-083 demonstrated synergistic efficacy with inhibitors of topoisomerase 1 (camptothecin) and topoisomerase 2 (etoposide) against multiple cancer cell lines. VAL-083’s ability to cross the blood-brain barrier and its ability to overcome common resistance mechanisms, combined with its radiotherapy-potentiating effects, suggest that VAL-083 may provide a new treatment option for DIPG and other pediatric CNS tumors as a single agent, in combination with radiotherapy, or as part of a combination regimen with topoisomerase inhibitors. We recently completed a phase I/II clinical trial in refractory GBM and established a well-tolerated dosing regimen of VAL-083 in adult brain tumor patients. In the present study, we investigated the effects of VAL-083 in combination with radiation or irinotecan (topoisomerase 1 inhibitor) in a panel of DIPG cell lines as well as patient-derived xenografts models. The results will guide a potential clinical trial of VAL-083 in treatment of DIPG, either as part of a chemo-radiation regimen or in combination with topoisomerase inhibitors. Citation Format: Anne Steino, Beibei Zhai, Beibei Zhai, Jeffrey Bacha, Dennis Brown, Shaun Fouse, Joe Costello, Mads Daugaard, Mads Daugaard, Sabine Mueller. Dianhydrogalactitol (VAL-083) has the potential to overcome major challenges in the treatment of DIPG [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr B30.
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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) | 0.004 | 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".