Activity of PU-H71, a novel HSP90 inhibitor, and bortezomib in Ewing sarcoma preclinical models.

3101 Background: Heat shock protein (HSP) 90 regulates the disposition and activity of a large number of deregulated proteins in Ewing sarcoma. We have shown pre-clinical efficacy of PU-H71, a novel HSP90 inhibitor developed at MSKCC, in Ewing sarcoma. Unfolded proteins as a result of HSP90 inhibition are degraded via the ubiquitin-proteasome pathway or the autophagy pathway. We investigated the effects of combined inhibition of HSP90 and the proteasome pathway. Methods: We studied the effects of PU-H71 and bortezomib alone and in combination on cell proliferation and viability in multiple Ewing cell lines, benign stromal cells and hematopoietic stem cells. We performed cell cycle analysis, clonogenic assay, immunoblot analysis, reverse phase protein array and in vivo experiments in NOD/SCID IL2R gamma null (NSG) mice using the A673 cell line transduced with GFP luciferase. Using A673 metastatic model in NSG mice, we investigated the disease burden when treated with PU-H71, bortezomib and in combination. ...