Abstract A46: HSP-90 inhibition in pediatric sarcomas

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Abstract Hsp90 is a molecular chaperone that regulates post-translational folding, stability, and function of many client proteins, which play critical roles in key signal transduction pathways implicated in cell growth, differentiation, and survival. Several relevant oncogenic proteins are described as clients, such as insulin growth factor receptor 1, AKT/PKB, and src-family kinases. Signaling through these molecules is critical in the biology of rhabdomyosarcoma and Ewing's sarcoma, which are two of the most common pediatric sarcomas. Novel therapies for these tumors are clearly needed since patients with relapsed and metastatic disease continue to have poor outcomes and multimodality therapy, even when successful, is often accompanied by long-term morbidity. Ganetespib (Synta Pharmaceuticals) is a small molecule Hsp90 inhibitor that binds to the ATP pocket in the N-terminus of Hsp90, leading to down-regulation of Hsp90 client protein levels. We sought to evaluate the preclinical activity of ganetespib in a panel of Ewing's Sarcoma and rhabdomyosarcoma cell lines. We evaluated in vitro activity of ganetespib in Ewing Sarcoma cell lines (TC71, TC32, EW8, RDES) and in rhabdomyosarcoma (RMS) cell lines (RD, RH30) using kinetic proliferation assays and MTS. In all cases, marked inhibition of cell growth was achieved in a dose-dependent manner with drug IC50s in the low nanomolar range (3-6 nM). We found that ganetespib exposure is associated with both induction of apoptosis and alterations in cell cycle progression. In addition to upregulation of Hsp70, which is considered a biomarker of Hsp90 inhibition, ganetespib treatment was associated with loss of expression of IGF1R-beta as well as downregulation of key signaling pathways including mammalian target of rapamycin (mTOR), pAKT, and Src-family kinases, particularly YES1, a kinase we previously identified as critical in rhabdomyosarcoma biology. Moreover, we observed a cooperative effect between Hsp90 inhibition and IGF1R blockade with R1507, a monoclonal antibody targeting this receptor (Hoffman-La Roche). Furthermore, synergy was seen when ganetespib was combined with the SFK inhibitor dasatinib. While in-vivo validation of these results is ongoing, we conclude that Hsp90 inhibition with ganetespib is an attractive strategy to explore for the therapy of pediatric sarcomas, possibly in combination with other targeted therapies. Citation Format: Fernanda I. Arnaldez, Toby Terwilliger, Choh Yeung, Len Neckers, Lee Helman. HSP-90 inhibition in pediatric sarcomas. [abstract]. In: Proceedings of the AACR Special Conference on Pediatric Cancer at the Crossroads: Translating Discovery into Improved Outcomes; Nov 3-6, 2013; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2013;74(20 Suppl):Abstract nr A46.