Direct Evidence of Target Inhibition with Anti- XXXX , @entity470 , and @entity3470 Therapies in a Clinical Model of Wound Healing.

@entity1 @entity137 @entity7 @entity5 @entity470 @entity2239 @entity319 @entity3470 @entity3866
PURPOSE: In early clinical testing, most novel targeted anticancer therapies have limited @entity137 and limited efficacy, which complicates dose and schedule selection for these agents. Confirmation of target inhibition is critical for rational drug development; however, repeated @entity5 biopsies are often impractical and peripheral blood mononuclear cells and normal skin are often inadequate surrogates for @entity5 tissue. Based upon the similarities of @entity5 and wound stroma, we have developed a clinical dermal granulation tissue model to evaluate novel targeted therapies. EXPERIMENTAL DESIGN: 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, @entity2239 , @entity3866 , and panitumumab, in the context of three different clinical trials. Total and phosphorylated levels @entity319 , S6RP, and @entity470 were evaluated using ELISA-based methodologies. RESULTS: Significant and consistent inhibition of the @entity7 pathway (using @entity319 as the readout) was observed in granulation tissue biopsies from @entity1 treated with bevacizumab and @entity2239 . In addition, significant and consistent inhibition of the @entity3470 pathway (using S6RP as the readout) was observed in @entity1 treated with @entity2239 . Finally, significant inhibition of the @entity470 pathway (using @entity470 as the readout) was observed in @entity1 treated with panitumumab, but this was not observed in @entity1 treated with @entity3866 . CONCLUSION: Molecular analyses of dermal granulation tissue can be used as a convenient and quantitative pharmacodynamic biomarker platform for multiple classes of targeted therapies. Clin Cancer Res; 1-11.   2015 AACR.
