Abstract PR19: Targeting DNA double-strand break repair to potentiate radio- and chemo-therapy of glioblastoma
Bibliographic record
Abstract
Abstract Glioblastomas (GBMs) are lethal brain tumors which are treated with ionizing radiation (IR) in combination with the DNA alkylating agent temozolomide (TMZ). Unfortunately, not all GBMs respond to therapy, and most of them quickly acquire resistance to TMZ and recur. In order to better understand the molecular basis for therapy-driven TMZ resistance, mice bearing orthotopic GBM xenografts were subjected to protracted TMZ treatment, and cell lines were generated from the primary (untreated) and recurrent (TMZ-treated) tumors. We found that cell lines derived from recurrent tumors were more resistant to TMZ in vitro compared to cell lines derived from primary tumors. We also found that the increased resistance to TMZ was due to augmented repair of TMZ-induced DNA double strand breaks (DSBs). TMZ induces DNA replication-associated DSBs that are primarily repaired by the homologous recombination (HR) pathway. Augmented HR appears to underpin TMZ resistance in the recurrent lines as these cells were cross-resistant to other agents that induce replication-associated DSBs, exhibited faster resolution of damage-induced Rad51 foci, and displayed higher levels of sister chromatid exchanges (SCEs). We have recently shown that CDKs 1 and 2 promote HR in S and G2 phases of the cell cycle, in part, by phosphorylating the exonuclease EXO1. We hypothesized, therefore, that blocking CDKs 1 and 2 might be a viable strategy for re-sensitizing recurrent tumors to TMZ. Indeed, we found that CDK inhibitors, AZD5438 and Roscovitine, could attenuate HR in the recurrent TMZ-resistant cell lines, resulting in significant chemo-sensitization. While TMZ-induced DSBs are primarily repaired by HR, IR- induced DSBs are mainly repaired by the non-homologous end joining (NHEJ) pathway. We, therefore, developed another approach to sensitize GBMs to both radiation and TMZ by using a dual PI3K/mTOR inhibitor, NVP-BEZ235, to target both DNA-PKcs and ATM, key enzymes in the NHEJ and HR pathways, respectively. We found that NVP-BEZ235 inhibited both DNA-PKcs and ATM in orthotopic GBM xenografts, thus blocking the repair of TMZ- and IR-induced DSBs in these tumors. Hence NVP-BEZ235, administered with IR, could attenuate tumor growth, and extend survival of tumor-bearing mice. Importantly, inhibition of DSB repair was more pronounced in tumor cells compared to normal brain cells, thereby providing a larger therapeutic window. In sum, these studies indicate that augmented DSB repair may underlie radio- and chemo-resistance in GBM, and provide support for DNA repair inhibition as an effective strategy for improving the efficacy of GBM therapy. This abstract is also being presented as Poster B22. Citation Format: Bipasha Mukherjee, Carlos Gil del Alcazar, Pavlina Todorova, Sandeep Burma. Targeting DNA double-strand break repair to potentiate radio- and chemo-therapy of glioblastoma [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 PR19.
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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 | 0.001 | 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".