Abstract 962: Prolonged antiangiogenic therapy with oral metronomic topotecan and pazopanib in pediatric solid tumor mouse model.
Bibliographic record
Abstract
Abstract Background: We have previously observed that the combination of daily oral Low Dose Metronomic (LDM) Topotecan (TP) and Pazopanib (PZ) significantly delayed the tumor growth and enhanced the survival in neuroblastoma (NB) mouse models (Kumar et al, 2011). However, this combination (TP+PZ) did not stop tumor growth and the animals eventually died due to disease during the course of therapy. Therefore, we planned to investigate the factors contributing to resistance to this antiangiogenic therapy in NB mouse model. Objectives: To investigate the effect of prolonged TP+PZ therapy on angiogenesis by testing the effect of therapy at different durations in NB mice xenograft model. Methods: Mice bearing subcutaneous SK-N-BE(2) NB xenografts were treated with either of the four regimens, daily, orally: vehicle (untreated), PZ (150 mg pazopanib), TP (1.0 mg/Kg topotecan), TP+PZ (combination of topotecan and pazopanib, same doses as single agents). Durations of treatment planned for each regimen were 28 days, 56 days and 80 days. Animals were sacrificed after these durations or upon end point, whichever was earlier. The criteria for end point are tumor sizes exceeding 2.0 cms in diameter or animals showing signs of morbidity. Results: The animals in control, PZ, TP reached the end point after 23d, 28d and 46d respectively. TP+PZ halted the tumor growth for up to 40 days, after which gradual growth was observed. The mean tumor diameters in the third TP+PZ group reached 1.8 cms at the day 80. CD31 immunofluorescence revealed that all the three durations of TP+PZ significantly lowered microvessel densities compared to the control (P= 0.02, 0.04 and 0.009 respectively for 28, 56 and 80 days respectively). However the ratio of CD31 to α- smooth muscle actin (pericyte marker) stained areas were significantly higher in animals treated with TP+PZ for 56 and 80days, compared to control (P=0.0006; 56d and 0.004; 80d) indicating higher pericyte coverage. TP+PZ (28d) showed signs of necrosis and cell cycle arrest (Ki67 staining), which were not observed in later durations (56 and 80 days) with TP+PZ. Long-term TP+PZ therapy also increased the levels of HIF-1 alpha, VEGF and Oct-4 within the tumor tissue. Conclusion: This study indicates that even though prolonged TP+PZ therapy demonstrates sustained antiangiogenic activity, it encounters resistance in NB, potentially mediated by pericyte coverage. Long-term TP+PZ therapy may also increase tumor stemness. Citation Format: Sushil Kumar, Reza Bayat Mokhtari, Syed Islam, Herman Yeger, Sylvain Baruchel. Prolonged antiangiogenic therapy with oral metronomic topotecan and pazopanib in pediatric solid tumor mouse model. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 962. doi:10.1158/1538-7445.AM2013-962
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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) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 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 | 0.002 |
| Insufficient payload (model declined to judge) | 0.002 | 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 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".