Abstract B28: Dianhydrogalactitol inhibits the growth of glioblastoma multiforme stem and non-stem cultures, in vitro and in vivo
Bibliographic record
Abstract
Abstract Glioblastoma multiforme (GBM) is the most common malignant brain cancer in adults and it presents some of the greatest challenges in the management of cancer patients worldwide. The standard of care for GBM patients is surgical resection followed by temozolomide (TMZ) and irradiation (XRT), but the prognosis for GBM patients remains poor, quality of life is low, and median survival for patients with recurrent GBM is <6 months. TMZ-resistance has emerged as a significant unmet medical need, as DNA repair enzyme 0-6-methylguanine DNA methyltransferase (MGMT) removes the TMZ-mediated methyl-group adducts at the O6 position of guanine. Dianhydrogalactitol (VAL-083) is a structurally unique bi-functional DNA alkylating agent that causes DNA crosslinks at the N7 position of guanine. VAL-083 crosses the blood brain barrier and accumulates in brain tumor tissue, and previous clinical trials suggest that VAL-083 has activity against a range of tumors, including GBM. Because VAL-083's N7 adducts are not subject to MGMT-mediated repair, it may be an effective chemotherapeutic in the treatment of TMZ-resistant GBM. We have recently shown that TMZ activity is similar in cancer stem cells (CSC) and their paired non-CSC from primary GBM tissues, and that the activity is MGMT-dependent. We thus sought to investigate how our CSC and non-CSC panel would respond to VAL-083 alone or in combination with XRT. We further investigated the activity of VAL-083 in in vivo models of drug-resistant GBM in comparison to TMZ. Rag2 mice bearing intracranial human GBM xenograft tumors of either MGMT-positive and TMZ-resistant origin (BT74), or MGMT-negative and TMZ-sensitive origin (U251) were treated. VAL-083 was given i.p. 3 times/week x 3 weeks, and the efficacy of VAL-083 in controlling tumor growth compared to TMZ (30 mg/kg). Disease progression was evaluated by overall survival, clinical observations and body weight measurements. Our in vitro results show that VAL-083 is a potent inhibitor of all tested primary GBM cultures, irrespective of MGMT status. VAL-083 causes cell cycle arrest and loss of cell viability in TMZ-resistant cells, and at lower concentrations than TMZ in TMZ-sensitive cells. Furthermore, VAL-083 is not affected by cell culture condition (Stem vs. Non-Stem). Low dose VAL-083 combined with XRT exhibited an additive effect in all cultures tested, suggesting that VAL-083 might act as a radiosensitizer. In the in vivo U251 model, the median survival time for mice treated with 4 mg/kg VAL-083 was significantly increased to 72 days compared to 48 days for controls (p<0.0001). Median survival time for 3 mg/kg VAL-083 was 54 days. Body weight loss was observed in mice treated with 5 mg/kg and treatment was stopped after 4 doses after which the animals recovered and their median survival was 57 days. Animals treated with TMZ were terminated at day 102 at the end of the study. BT74: study is ongoing, data will be presented at the meeting. In conclusion, VAL-083 is highly efficacious against both stem and non-stem GBM cell cultures in vitro, the activity is independent of MGMT and VAL-083 appears to act as a radiosensitizer in GBM. In vivo xenograft GBM models further validate the benefits of VAL-083 in the treatment of GBM and support ongoing clinical research with VAL-083, which is currently in a clinical trial for GBM patients with recurrent disease. Citation Format: Shaun D. Fouse, Anne Steino, Nicholas Butowski, Jeffrey A. Bacha, Sarath Kanekal, Nancy Dos Santos, Joseph F. Costello, Dennis M. Brown. Dianhydrogalactitol inhibits the growth of glioblastoma multiforme stem and non-stem cultures, in vitro and in vivo. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr B28.
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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".