Abstract 2506: Preclinical evaluation of sorafenib in combination with ionizing radiation in metastatic breast cancer model
Bibliographic record
Abstract
Abstract Sorafenib tosylate (Bay 54-9085) is an oral, small molecule multikinase inhibitor of several targets including RAF/MEK/ERK signaling, vascular endothelial growth factor receptor-2 (VEGFR-2), VEGFR-3, and platelet derived growth factor receptor-beta (PDGFR-b). Sorafenib has shown clinical efficacy in solid tumors such as renal cell and hepatocellular carcinomas. Retrospective analysis of breast cancer patients has shown an unfavorable prognosis in patients with high expression level of VEGF, indicating that VEGF could be associated with efficacy of chemotherapy and radiotherapy. It has also been shown that radiation resistance is partially due to tumor cell production of angiogenic cytokines, particularly VEGF that protects endothelial cells through survival pathways. The aim of this study is to investigate if radiation response is enhanced through inhibition of p-VEGFR2/PDGFR-b by Sorafenib and if the combination of Sorafenib and radiation will increase the treatment response in a metastatic breast cancer model. Mouse metastatic mammary cancer cells, 4T1 were used in this study. Clonogenic assay was performed to assess the radiomodulating effect of Sorafenib. In addition, cell cycle analysis and annexin-V binding assay were performed 24 and 48 hrs post treatment respectively. To confirm our in vitro data, a tumor growth delay assay was completed in a syngeneic mouse model. Western blot analysis showed strong dose dependent inhibition of ERK1/2 phosphorylation by sorafenib. Our clonogenic assay showed a supra-additive effect of Sorafenib (7.5 μM) and radiation (4 Gy) with a dose enhancement factor (DEF) of 1.81. Sorafenib in combination with radiation demonstrated a significant G2/M cell cycle arrest (p<0.0001). Moreover, annexin-V staining assay showed a significant increase in the level of apoptosis in cells treated with both sorafenib and radiation (p<0.0004). Our in vivo results strongly suggest that radiation prolongs the anti tumor activity of sorafenib. In addition, tumor growth was delayed when radiation was combined with sorafenib concurrently (tumor growth delay was increased from 10.5 days in irradiated group to 18 days in combined treatment group). Our results demonstrate that sorafenib increases both the level of apoptosis and the sensitivity of 4T1 cancer cells to radiation. The higher potency of sorafenib combined with radiation can be partially due to the strong cell cycle arrest at G2/M phase. Moreover, our in vivo results show that sorafenib in combination with radiation exhibit a superior tumor growth control. Overall, our findings suggest that greater treatment response may be achieved when sorafenib is combined with radiation. More studies are being conducted to investigate the optimal schedule for this combination. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2506. doi:10.1158/1538-7445.AM2011-2506
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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".