Abstract 5210: KPT-330, a selective small molecule inhibitor of nuclear export, is active in bone and soft tissue sarcoma.

Abstract

Abstract KPT-330 is a small molecule Selective Inhibitor of Nuclear Export (SINE) that irreversibly block the major nuclear export protein CRM1 (exportin 1, XPO1). The Chromosome Region Maintenance 1 (CRM1) protein is responsible for the nuclear export of snRNAs and of proteins bearing a leucine-rich nuclear export signal (NES). This class of drugs is expected to induce forced nuclear accumulation of tumor suppressor proteins (TSPs) and is believed to initiate a ‘genome survey’ leading to the death of cancer cells with normal cells undergoing transient, reversible cell cycle arrest. Our effort was to investigate the effects of KPT-330 in sarcomas and the mechanism by which it exerts the effect of tumor suppression. Our data clearly shows KPT-330 as active against a broad panel of human bone and soft tissue sarcoma cell lines at low nanomolar concentrations. The effect was mainly due to the induction of apoptosis. Target specificity of the drug was confirmed by the decrease in CRM1 protein level. An induction of p53 and p21 protein levels was observed. However, the effect of apoptosis or inhibition in proliferation seems to be independent of p53 status of the cell line. The effect of KPT-330 was further tested in xenograft models using malignant peripheral nerve sheath (MPNST) and de-differentiated liposarcoma (LS141) cell lines. Tumor suppression was observed in both the sarcoma models and its target specificity was confirmed in the xenografts. KPT-330 may represent a new drug for the treatment of bone and soft tissue sarcoma. Citation Format: Jayasree S. Nair, William Tap, Shyamprasad Deraje Vasudeva, Jason K. Sicklick, Michael Kauffman, Sharon Shacham, Gary K. Schwartz. KPT-330, a selective small molecule inhibitor of nuclear export, is active in bone and soft tissue sarcoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 5210. doi:10.1158/1538-7445.AM2013-5210