title: Potential histologic and molecular predictors of response to temsirolimus in patients with advanced renal cell carcinoma.
abstract: OBJECTIVE
  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.
  
  
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Beth 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
authors.forename: Daniel
authors.initials: D
authors.lastname: Cho
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.forename: Sandra
authors.initials: S
authors.lastname: Dabora
authors.forename: Meredith
authors.initials: M
authors.lastname: Regan
authors.forename: Apryle
authors.initials: A
authors.lastname: Seeley
authors.forename: Mauro
authors.initials: M
authors.lastname: Mariotti
authors.forename: Amanda
authors.initials: A
authors.lastname: Youmans
authors.forename: Adam
authors.initials: A
authors.lastname: Polivy
authors.forename: Lucy
authors.initials: L
authors.lastname: Mandato
authors.forename: David
authors.initials: D
authors.lastname: McDermott
authors.forename: Eric
authors.initials: E
authors.lastname: Stanbridge
authors.forename: Michael
authors.initials: M
authors.lastname: Atkins
mesh_terms: D000951:Antigens, Neoplasm / Q000378:metabolism; D014408:Biomarkers, Tumor / Q000378:metabolism*; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases / Q000378:metabolism; D002292:Carcinoma, Renal Cell / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D017322:Clinical Trials, Phase II as Topic; D005260:Female; D006801:Humans; D007124:Immunoenzyme Techniques; D007680:Kidney Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D008297:Male; D009154:Mutation / Q000235:genetics; D051059:PTEN Phosphohydrolase / Q000378:metabolism; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000627:therapeutic use*; D011494:Protein Kinases / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016032:Randomized Controlled Trials as Topic; D020123:Sirolimus / Q000031:analogs & derivatives* / Q000627:therapeutic use; D058570:TOR Serine-Threonine Kinases; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D000951:Antigens, Neoplasm; D014408:Biomarkers, Tumor; D047428:Protein Kinase Inhibitors; C401859:temsirolimus; D051794:Von Hippel-Lindau Tumor Suppressor Protein; D011494:Protein Kinases; C546842:MTOR protein, human; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; D051059:PTEN Phosphohydrolase; C494929:PTEN protein, human; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX; D002256:Carbonic Anhydrases; C497446:VHL protein, human; D020123:Sirolimus