Overcoming sunitinib-induced resistance by dose escalation in renal cell carcinoma: Evidence in animal models and patients.
Bibliographic record
Abstract
4582 Background: Sunitinib is considered a first-line therapeutic option for patients with advanced clear cell renal cell carcinoma (ccRCC). However, despite the clinical efficacy, eventually tumors develop resistance and progress. Thus, we have tested the hypothesis whether sunitinib dose-escalation could overcome initial drug resistance. Methods: Human patient-derived ccRCC xenografts were implanted in SCID mice and were randomly assigned into two groups (sunitinib and vehicle). Mice were treated with sunitinib 5 days/week with a dose-escalation schema starting from 40 mg/kg to 60 mg/kg and 80 mg/kg. Tumor volumes and body weights were assessed weekly. Tumor tissues and blood were collected prior to dose increments. In selected patients treated with 50 mg sunitinib and presenting minimal toxicities, dose was escalated to 62.5 and 75 mg at the time of tumor progression. Results: Our preclinical results show that patient-derived tumors (RP-01 and RP-02), although initially responsive to sunitinib 40 mg/kg, eventually became resistant to treatment. Following dose increase to 60 mg/kg, we observed again tumor response but eventually the tumors became resistant. A similar effect was noticed when we further escalated sunitinib to 80 mg/kg. Immunohistochemistry analysis shows decreased tumor vascularization during response to sunitinib, but then hypervascularization at the time of resistance. Associated increase in expression of the methyltransferase EZH2, the histone marks H3K27me3, H3k4me2 and H3K9me2 in tumors resistant to sunitinib was observed. Analysis of sunitinib and VEGF/VEFGR2 blood and tumor levels will be reported. In parallel, our clinical experience shows that intra-patient sunitinib dose-escalation was safe and clinical benefit was observed. Details on tumor responses and toxicities will be reported. Conclusions: Overall, our results suggest that sunitinib-induced resistance may be overcome in part by increasing the dose of the VEGF receptor tyrosine kinase inhibitor in mouse models and ccRCC patients, and highlights the potential role of epigenetic changes associated with sunitinib resistance.
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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 | 0.001 | 0.000 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| 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 | 0.001 |
| Insufficient payload (model declined to judge) | 0.001 | 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".