Abstract B27: Co-inhibition of ATM and TDP1 as a novel chemosensitization strategy against malignant brain tumors
Bibliographic record
Abstract
Abstract Purpose: Current methods to treat glioblastoma multiforme (GBM) are highly invasive, lead to poor quality-of-life and an abysmal patient survival rate thus making GBMs one of the most difficult-to-treat and deadliest form of all primary CNS malignancies. The targeted use of Topoisomerase-1 (Top1) poisons/inhibitors to sensitize or augment tumor cell killing is a long-standing and powerful tool in cancer therapy. A number of trials utilizing Top1 inhibitors to manage GBM have shown promise. We have uncovered a novel functional requirement for ATM (Mutated in Ataxia Telangiectasia) in resolving oxidative DNA breaks and Topoisomerase 1-DNA covalent complexes (Top1cc), a DNA-protein intermediate that can generate DNA breaks upon collision with the transcriptional machinery or DNA replication forks. These data have identified Top1cc as the first specific endogenous pathogenic neural DNA lesion associated with loss of ATM and heritable pediatric neurodegenerative disease. Furthermore, biochemical and genetic studies identified collaboration of ATM and TDP1 (Tyrosyl-DNA Phosphodiesterase 1) in the resolution of Top1cc during neurodevelopment. We hypothesize that co-inhibition of ATM and TDP1 will sensitize brain tumors to Top1-dependent chemotherapy by augmenting Top1cc levels and anti-tumor success. Methods: Genetic and biochemical methods to co-inhibit ATM and TDP1 and improve the efficacy of Top1 poisons include novel high-throughput cell-based DNA damage repair and viability assays and in vivo brain tumor regression assays using mouse xenograft models. Results: We have found that brain tumor cell killing via Top1-dependent inhibition is greatly enhanced through an ATM and TDP1 co-inhibition strategy. Induced genotoxic cell death occurs at lower chemotherapeutic drug doses as a result of sensitization to Top1cc. We are presently validating these results and performing in vivo studies. Conclusions: ATM and TDP1 co-inhibition represents an effective two-pronged approach to chemoradiosensitize CNS tumors. As TDP1 antagonizes Top1cc formation and efficacy of Top1 poisons such as the camptothecin (CPT) cohort of drugs, our findings will improve existing Top1-mediated anti-cancer strategies by enhancing tumor cell killing while reducing clinical doses and patient side-effects. Furthermore, these findings also suggest an alternative avenue in the clinical management of GBM. Citation Format: Matthew Packer, Ali Saleh, Sachin Katyal. Co-inhibition of ATM and TDP1 as a novel chemosensitization strategy against malignant brain tumors [abstract]. In: Proceedings of the AACR Special Conference on DNA Repair: Tumor Development and Therapeutic Response; 2016 Nov 2-5; Montreal, QC, Canada. Philadelphia (PA): AACR; Mol Cancer Res 2017;15(4_Suppl):Abstract nr B27.
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How this classification was reachedexpand
Full frame distilled prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. Learned from the 10,348 direct Codex labels and 10,348 direct Gemma labels. Candidate is the union of thresholded teacher heads; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels or direct frontier model labels.
Codex and Gemma teacher scores by category
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.001 | 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) | 0.000 | 0.000 |
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 teacher head, 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".