Abstract A51: Dianhydrogalactitol (VAL-083) offers potential therapeutic alternatives in the treatment of pediatric brain tumors
Bibliographic record
Abstract
Abstract Background: Medulloblastoma (MB) is the most common malignant pediatric brain tumor, accounting for 15-30% of all childhood intracranial neoplasms. High grade gliomas (HGG) are much rarer in children than in adults, comprising only 5%-10% of childhood brain tumors. Although multidisciplinary treatment has improved the 5-year survival rates in children significantly, the prognosis for recurrent MB and HGG remains poor with median overall survival <1 year. Temozolomide (TMZ) is frequently employed in the treatment of MB and pediatric HGG; however, clinical evidence is lacking and poor outcomes due to high-expression of the repair protein O6-methylguanine-DNA methyltransferase (MGMT), which is correlated with TMZ resistance, have been reported. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional alkylating agent causing DNA crosslinks at N7 position of guanine. VAL-083 readily crosses the blood brain barrier and has been shown to accumulate in brain tumor tissue. Furthermore, VAL-083 demonstrated clinical activity against MB and HGG in historical NCI-sponsored clinical studies. We have recently shown that VAL-083 demonstrates cytotoxic activity in GBM independent of MGMT expression in vitro and in vivo. We have further shown that VAL-083 is highly effective against GBM cancer stem cells (CSC) and non-CSC and that it acts as a radiosensitizer in GBM cell lines, in vitro. VAL-083 is currently in phase II clinical trials for recurrent GBM in adults. In the current adult GBM clinical trial VAL-083 displayed a favorable safety-profile and preliminary analysis supports a survival benefit at doses chosen for further investigation. Based on these recent results and data supporting VAL-083's clinical activity in historical MB and HGG studies, we sought to investigate the cytotoxic activity of VAL-083 as a potential therapeutic alternative for pediatric brain tumors by studying the drug against MB and pediatric HGG cell lines in vitro. Methods: Human MB cell lines DAOY, UW228, ONS-76 and UW426 and pediatric HGG cell line SF188 were treated with VAL-083 at concentrations of 0.1 100 μM for 72 h. Growth inhibition was measured by high content screening analysis. Neurosphere formation of DAOY and SF188 cells was determined by neurosphere colony assay. Results: VAL-083 inhibited growth of all cell lines (DAOY, UW228, ONS-76 UW426 and SF188) with IC50 at low micro-molar concentrations. DAOY, UW228 and SF188 cells were most sensitive to VAL-083. Primary neurosphere formation of DAOY cells was completely inhibited at 5 μM VAL-083 and VAL-083 was superior to TMZ against primary neurospheres formation of SF-188 cells; complete inhibition of SF-188 neurospheres was observed with the combination of VAL-083 and TMZ. Conclusion: These results suggest that VAL-083 is active against MB and pediatric HGG cells as well as CSC in vitro. Taken together with the results of historical NCI-sponsored clinical trials, these data warrant further investigations of VAL-083 as a possible therapeutic alternative for the treatment of recurrent pediatric MB and HGG. Citation Format: Jeffrey A. Bacha, Abbas Fotovati, Kaiji Hu, Anne Steino, Sarath Kanekal, Dennis M. Brown. Dianhydrogalactitol (VAL-083) offers potential therapeutic alternatives in the treatment of pediatric brain tumors. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Pediatric Cancer Research: From Mechanisms and Models to Treatment and Survivorship; 2015 Nov 9-12; Fort Lauderdale, FL. Philadelphia (PA): AACR; Cancer Res 2016;76(5 Suppl):Abstract nr A51.
Fetched live from OpenAlex and de-inverted. Abstracts are not stored in this database: the inverted indexes are 8.6 GB of the frame’s 9.3 GB of text, and the host has 13 GB free.
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".