title: Direct Evidence of Target Inhibition with Anti-VEGF, EGFR, and mTOR Therapies in a Clinical Model of Wound Healing.
abstract: OBJECTIVE
  In early clinical testing, most novel targeted anticancer therapies have limited toxicities and limited efficacy, which complicates dose and schedule selection for these agents. Confirmation of target inhibition is critical for rational drug development; however, repeated tumor biopsies are often impractical and peripheral blood mononuclear cells and normal skin are often inadequate surrogates for tumor tissue. Based upon the similarities of tumor and wound stroma, we have developed a clinical dermal granulation tissue model to evaluate novel targeted therapies.
  
  
  METHODS
  A 4-mm skin punch biopsy was used to stimulate wound healing and a repeat 5-mm punch biopsy was used to harvest the resulting granulation tissue. This assay was performed at pretreatment and on-treatment evaluating four targeted therapies, bevacizumab, everolimus, erlotinib, and panitumumab, in the context of three different clinical trials. Total and phosphorylated levels VEGFR2, S6RP, and EGFR were evaluated using ELISA-based methodologies.
  
  
  RESULTS
  Significant and consistent inhibition of the VEGF pathway (using VEGFR2 as the readout) was observed in granulation tissue biopsies from patients treated with bevacizumab and everolimus. In addition, significant and consistent inhibition of the mTOR pathway (using S6RP as the readout) was observed in patients treated with everolimus. Finally, significant inhibition of the EGFR pathway (using EGFR as the readout) was observed in patients treated with panitumumab, but this was not observed in patients treated with erlotinib.
  
  
  CONCLUSIONS
  Molecular analyses of dermal granulation tissue can be used as a convenient and quantitative pharmacodynamic biomarker platform for multiple classes of targeted therapies.
authors: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina.
authors: Jingquan
authors: J
authors: Jia
authors: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
authors: Andrew E
authors: AE
authors: Dellinger
authors: Temple University School of Medicine, Philadelphia, Pennsylvania.
authors: Eric S
authors: ES
authors: Weiss
authors: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
authors: Anuradha
authors: A
authors: Bulusu
authors: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina.
authors: Christel
authors: C
authors: Rushing
authors: Department of Medicine, Center for Musculoskeletal Research, University of Rochester Medical Center, Rochester, New York.
authors: Haiyan
authors: H
authors: Li
authors: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina.
authors: Leigh A
authors: LA
authors: Howard
authors: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina.
authors: Neal
authors: N
authors: Kaplan
authors: Department of Biostatistics and Bioinformatics, Duke University Medical Center, Durham, North Carolina. School of Public Health, Li Ka Shing Faculty of Medicine, The University of Hong Kong, Pok Fu Lam, Hong Kong SAR, China.
authors: Herbert
authors: H
authors: Pang
authors: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina.
authors: Herbert I
authors: HI
authors: Hurwitz
authors: Department of Medicine, Division of Medical Oncology, Duke University Medical Center, Durham, North Carolina. anixon@duke.edu.
authors: Andrew B
authors: AB
authors: Nixon
mesh_terms: D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000008:administration & dosage; D000068258:Bevacizumab / Q000008:administration & dosage; D001707:Biopsy, Needle; D002986:Clinical Trials as Topic; D018572:Disease-Free Survival; D004353:Drug Evaluation, Preclinical; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics; D000069347:Erlotinib Hydrochloride / Q000008:administration & dosage; D000068338:Everolimus / Q000008:administration & dosage; D005260:Female; D006097:Granulation Tissue / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D008297:Male; D008875:Middle Aged; D000077544:Panitumumab; D012867:Skin / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors* / Q000235:genetics; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000096:biosynthesis* / Q000235:genetics; D014945:Wound Healing / Q000187:drug effects*
chemical_list: D000911:Antibodies, Monoclonal; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D000077544:Panitumumab; D000068338:Everolimus; D000069347:Erlotinib Hydrochloride; C546842:MTOR protein, human; C512478:EGFR protein, human; D066246:ErbB Receptors; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2; D058570:TOR Serine-Threonine Kinases