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Updated: Jul 10, 2026
A Syngeneic Mouse Model of Metastatic Renal Cell Carcinoma for Quantitative and Longitudinal Assessment of Preclinical Therapies
Published on: April 12, 2017
Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell
Daniel Cho1, Sabina Signoretti, Sandra Dabora
1Beth Israel Deaconess Medical Center, Boston, MA 02215, and Department of Microbiology and Molecular Genetics, University of California, Irvine College of Medicine, USA. dcho1@bidmc.harvard.edu
Purpose:
Similar to other molecularly targeted agents, temsirolimus, an inhibitor of mammalian target of rapamycin, has shown promising activity in advanced renal cell carcinoma. However, only a subset of patients appears to derive significant tumor responses. In an effort to identify potential predictors of response to temsirolimus, tumor samples from a subset of patients within a randomized phase II trial of temsirolimus in advanced renal cell carcinoma were studied.
Patients And Methods:
Paraffin-embedded tissue sections from patients who had received temsirolimus were immunostained with antibodies to carbonic anhydrase IX, phospho-S6, phospho-Akt (pAkt), and phosphotase and tensin homologue. Expression levels were correlated with objective response (partial response [PR], minor response [MR]) and clinical benefit (PR, MR, SD>or=4 cycles) to temsirolimus. In addition, von Hippel-Lindau (VHL) mutational analysis was performed and correlated with response.
Results:
Tissue specimens were obtained from 20 patients who were evaluable for both tumor response and staining for phospho-S6 and carbonic anhydrase IX. In addition, 19 specimens were evaluable for pAkt, and 18 for phosphotase and tensin homologue. VHL mutational analysis was performed on 16 samples. Five patients achieved an objective response (1 PR/4 MRs) to temsirolimus. There was a positive association of phospho-S6 expression (P=.02) and a trend toward positive expression of pAkt (P=.07) with response to temsirolimus. No patient without high expression of either phospho-S6 or pAkt experienced an objective tumor response. There was no correlation of carbonic anhydrase IX and phosphotase and tensin homologue expression or VHL status with response to temsirolimus.
Conclusion:
These results suggest that phospho-S6 and pAkt expression are promising predictive biomarkers for response to temsirolimus that are worthy of further exploration for use in patient selection models for mammalian target of rapamycin inhibitors.
Insights
Phospho-S6 and phospho-Akt (pAkt) expression in tumors predict response to temsirolimus, a mammalian target of rapamycin inhibitor, in advanced renal cell carcinoma. These biomarkers can help select patients likely to benefit from this targeted therapy.
Area of Science:
- Oncology
- Molecular Biology
- Biomarker Discovery
Background:
- Temsirolimus, a mammalian target of rapamycin (mTOR) inhibitor, shows activity in advanced renal cell carcinoma (RCC).
- Patient response to temsirolimus varies, necessitating identification of predictive biomarkers.
- Understanding molecular predictors can optimize treatment strategies for RCC.
Purpose of the Study:
- To identify potential predictive biomarkers for response to temsirolimus in advanced RCC.
- To investigate the association between carbonic anhydrase IX, phospho-S6, phospho-Akt (pAkt), and phosphotase and tensin homologue expression, and VHL status with temsirolimus response.
- To correlate these molecular markers with objective response and clinical benefit.
Main Methods:
- Immunohistochemical staining of tumor samples for carbonic anhydrase IX, phospho-S6, pAkt, and phosphotase and tensin homologue.
- Correlation of protein expression levels with objective response (PR, MR) and clinical benefit.
- Von Hippel-Lindau (VHL) mutational analysis of tumor samples.
- Analysis of data from a randomized phase II trial of temsirolimus in advanced RCC patients.
Main Results:
- High phospho-S6 expression was significantly associated with objective response to temsirolimus (P=.02).
- A trend towards positive association was observed for pAkt expression (P=.07).
- No objective response was observed in patients lacking high phospho-S6 or pAkt expression; carbonic anhydrase IX, phosphotase and tensin homologue, and VHL status did not correlate with response.
Conclusions:
- Phospho-S6 and pAkt expression are promising predictive biomarkers for temsirolimus response in advanced RCC.
- These biomarkers warrant further investigation for patient selection in mTOR inhibitor therapy.
- Biomarker-guided patient selection could improve outcomes in RCC treatment.
