Abstract IA22: The role of ATM in tumor and endothelial cells in mediating the response of cancer to radiation therapy
Bibliographic record
Abstract
Abstract Fibroblasts isolated from patients with ataxia telangiectasia are exquisitely sensitive to ionizing radiation and mice lacking the gene mutated in ataxia telangiectasia (ATM) are sensitive to total-body irradiation. Kinase inhibitors of ATM can sensitize tumor cells to radiation, but these inhibitors may also sensitize normal tissues to radiation toxicity. Endothelial cell damage can contribute to the development of long-term side effects after radiation therapy, but whether endothelial cell death plays an important role in tumor response to radiation therapy has remained unclear. To clarify the role of endothelial cells in the response of cancer to radiation therapy, we employed dual recombinase technology using both FlpO and Cre recombinases to generate primary sarcomas in mice with endothelial cell-specific deletion of Atm. Deletion of Atm in proliferating tumor endothelial cells increased endothelial cell death after radiation therapy and enhanced the response of primary sarcomas to radiation as measured by tumor growth delay. However, deletion of Atm from endothelial cells failed to enhance sarcoma eradication as no difference was observed when a higher radiation dose was utilized with local control as the endpoint. In contrast, deletion of Atm from tumor cells increased sarcoma eradication by radiation therapy. These results demonstrate that tumor cells, rather than endothelial cells, are critical targets that regulate sarcoma eradication by radiation therapy. Interestingly, Atm deletion in quiescent endothelial cells of the heart did not sensitize mice to radiation-induced myocardial necrosis. However, in mice lacking p53 in endothelial cells, which are sensitized to radiation-induced injury to the heart, deletion of ATM in addition to p53 further enhanced radiation sensitivity following whole-heart irradiation. Taken together, these genetic experiments suggest that targeting ATM during radiotherapy may provide a therapeutic gain for tumors lacking p53 function particularly when the tumor is located at an anatomic site where the adjacent normal tissue is quiescent. To test this model in mice using a pharmacological approach, we treated mice with BEZ235, which is a small molecule inhibitor of several PI3-kinase family kinases including ATM. BEZ235 sensitized primary sarcomas to radiation therapy, but only enhanced radiation-induced heart disease when p53 was deleted from endothelial cells. These results suggest that inhibiting ATM kinase during radiation therapy is a viable strategy for radiosensitization of some tumors. Citation Format: David Kirsch. The role of ATM in tumor and endothelial cells in mediating the response of cancer to radiation therapy [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 IA22.
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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 | 0.002 | 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".