Abstract 3440: CRM1-Selective Inhibitors of Nuclear Export (SINE) reduce the incidence of tumor spreading and improve overall survival in preclinical models of prostate cancer. (2013)

Abstract Background: CRM1 (XPO1) is the exclusive exportin mediating transport of most tumor suppressor proteins (TSPs) including p53, pRb, FOXO, APC and p21 out of the nucleus, abrogating their function. Methods: We tested the effects of the potent, selective, clinical stage oral SINE compound KPT-330 in prostate cancer (PrCa) models. Male SCID mice orthotopically (intraprostatic) inoculated with the DU145 PrCa, known to produce highly metastatic tumors with visceral metastases. In parallel, male CD1-nu/nu mice were inoculated with intracardiac and intratibial injections of the aggressive/bone-derived PrCa PC3, known to produce prominent osteolytic bone lesions. The effects of SINEs KPT-330 and KPT-251 on metastatic spreading were determined. Results: We previously demonstrated that SINE CRM1 antagonists KPT330 and KPT251 have potent antitumor effects on PrCa both in vitro and in vivo. Here, we demonstrate that KPT-330 reduces intraprostatic DU145 tumor burden as well as the incidence of macroscopic metastases to lymph nodes, liver and lung, in a dose-dependent manner. The DU145 tumor burden was reduced by 41% with KPT-330 (4 mg/kg qd/5 days) and 61% (10 mg/kg q 3-4 d x 7) when compared to controls. The incidence of PC3-derived bone metastases were significantly reduced with KPT-330 at 10 mg/kg (q 2d x 3 weeks). At 50 days after cell injection, 80% (8/10) of controls and 0% (0/10) of the KPT-330-treated animals developed X-Ray evidence of bone lesions (p&amp;lt;0.05). The burden of bone metastases, measured by lytic bone area, was significantly higher in controls than in KPT-330-treated animals. Similarly, after intra-tibial injection, the lytic areas were higher in controls than in the KPT-330 group (p&amp;lt;0.05). The level of serum markers of osteoclast activity (TRAP and type I collagen fragment, CTX), was significantly higher in controls than in KPT-330-treated animals. The related SINE KPT-251 (100 mg/Kg q 2d x 3 weeks) confirmed the reduction of bone metastasis following CRM1 inhibition. The overall and disease free survival, evaluated at 170 days after tumor injection, were significantly higher in KPT-330- and KPT-251-treated animals versus controls (P&amp;lt; 0.0001). Treatment of PC3 and DU145 cells with KPT-330 lead to significant reductions in the secretion of proteolytic enzymes (MMP-9, MMP-2, uPA) as well as reduced ability of tumor cells to migrate and invade Matrigel. Impaired secretion of pro-angiogenic (VEGF, IL6, IL8) and pro-osteolytic (RANKL, IL6) cytokines was also observed. Conclusions: These data show that selective blockade of CRM1-dependent nuclear export has direct antitumor, anti-metastatic and anti-osteolytic activities in PrCa and thus represents a novel approach for the treatment of advanced/ metastatic PrCa. KPT-330 is now in Phase 1 clinical trials in patients with advanced solid tumors (clinicaltrailas.gov: NCT01607905). Citation Format: Giovanni Luca Gravina, Monica Tortoreto, Andrea Mancini, Paola Muzi, Luca Ventura, Sandra D'ascenzo, Alessandro Addis, Yosef Landesman, Dilara McCauley, Vincenza Dolo, Michael Kauffman, Sharon Shacham, Nadia Zaffaroni, Claudio Festuccia. CRM1-Selective Inhibitors of Nuclear Export (SINE) reduce the incidence of tumor spreading and improve overall survival in preclinical models of prostate 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 3440. doi:10.1158/1538-7445.AM2013-3440