Abstract
Background: CRM1 is a nuclear export protein which increases cell viability through nuclear export signal-dependent protein exclusion of tumor suppressor proteins. Selective Inhibitor of Nuclear Exprot (SINE) is a novel class of drugs that selectively inhibit CRM1. Here, we tested the biological effects of targeting CRM1. Methods and results: To explore the efficacy of SINE CRM1 anatgonists in ovarian cancer, we tested the selective small molecule KPT-185(in vitro) against human ovarian cancer cell lines. KPT-185 reduced cell viability in multiple (A2780, A2780CP20, IGROV-1 and SKOV3) human ovarian cancer cell lines with IC50 levels ranging from 0.2 - 0.75μM. Nuclear localization and significantly increased expression of tumor suppressor proteins (e.g., p53, p21 and Fox03a) was noted in response to KPT-185 treatment. Moreover, synergistic reduction in cell viability was noted with topotecan, cisplatin and liposomal doxorubicin (interaction index was 0.45, 0.78 and 0.59, respectively). Using the A2780 in vivo orthotopic ovarian cancer model, oral administration of KPT-330 (in vivo) monotherapy at 20mg/kg twice a week resulted in 90% tumor reduction (p<0.01). In combination with topotecan, there was 98% reduction (p<0.01) in tumor growth. KPT-330 also showed significant tumor growth inhibition in combination with weekly paclitaxel or bevacizumab. Histological examination of obtained tumor samples showed 2.5-fold increase in number of caspase-3 positive cells (p<0.01) and 0.4-fold decreased of Ki67 positive cells (p<0.05) in KPT-330 treated group. In each experiment, KPT-330 was well tolerated and no significant changes in mouse body weight were noted. Conclusion: CRM1 inhibitor is a potent inhibitor of ovarian cancer growth and merits additional development. Citation Format: Takahito M. Miyake, Sunila Pradeep, Behrouz Zand, Heather J. Dalton, Yunfei Wen, Guillermo N. Armaitz Pena, Michael Kauffman, Dilara McCauley, Sharon Shacham, John E. Wiktorowicz, Anil K. Sood. Therapeutic targeting of CRM1 in ovarian cancer. [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 5541. doi:10.1158/1538-7445.AM2013-5541