XPO1/CRM1-Selective Inhibitors of Nuclear Export (SINE) reduce tumor spreading and improve overall survival in preclinical models of prostate cancer (PCa)

Journal of Hematology & Oncology

Claudio Festuccia²  Nadia Zaffaroni⁴  Sharon Shacham³  Michael Kauffman³  Dilara McCauley³  Yosef Landesman³  Andrea Lenzi⁵  Ernesto Di Cesare¹  Alessandro Addis⁴  Andrea Mancini²  Monica Tortoreto⁴  Giovanni Luca Gravina⁵ 

[1] Department of Biotechnological and Applied Clinical Sciences, Division of Radiotherapy, University of L’Aquila, L’Aquila, Italy;Department of Biotechnological and Applied Clinical Sciences, Laboratory of Radiobiology, University of L’Aquila, L’Aquila, Italy;Karyopharm Therapeutics, Natick, MA, USA;Department of Experimental Oncology and Molecular Medicine, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy;Department of Experimental Medicine, Pathophysiology Section, Sapienza University of Rome, Rome, Italy

关键词: Selinexor;    KPT-330;    CRM1;    XPO1;    Tumor suppressor protein;    Bone metastases;    Prostate cancer;   

Others  :  1144222
DOI  :  10.1186/1756-8722-7-46

 received in 2014-05-03, accepted in 2014-06-19,  发布年份 2014

【 摘 要 】

Background

Exportin 1 (XPO1), also called chromosome region maintenance 1 (CRM1), is the sole exportin mediating transport of many multiple tumor suppressor proteins out of the nucleus.

Aim and methods

To verify the hypothesis that XPO1 inhibition affects prostate cancer (PCa) metastatic potential, orally available, potent and selective, SINE compounds, Selinexor (KPT- 330) and KPT-251, were tested in preclinical models known to generate bone lesions and systemic tumor spread.

Results

In vitro, Selinexor reduced both secretion of proteases and ability to migrate and invade of PCa cells. SINEs impaired secretion of pro-angiogenic and pro-osteolytic cytokines and reduced osteoclastogenesis in RAW264.7 cells. In the intra-prostatic growth model, Selinexor reduced DU145 tumor growth by 41% and 61% at the doses of 4 mg/Kg qd/5 days and 10 mg/Kg q2dx3 weeks, respectively, as well as the incidence of macroscopic visceral metastases. In a systemic metastasis model, following intracardiac injection of PCb2 cells, 80% (8/10) of controls, 10% (1/10) Selinexor- and 20% (2/10) KPT-251-treated animals developed radiographic evidence of lytic bone lesions. Similarly, after intra-tibial injection, the lytic areas were higher in controls than in Selinexor and KPT-251 groups. Analogously, the serum levels of osteoclast markers (mTRAP and type I collagen fragment, CTX), were significantly higher in controls than in Selinexor- and KPT-251-treated animals. Importantly, overall survival and disease-free survival were significantly higher in Selinexor- and KPT-251-treated animals when compared to controls.

Conclusions

Selective blockade of XPO1-dependent nuclear export represents a completely novel approach for the treatment of advanced and metastatic PCa.

【 授权许可】

   
2014 Gravina et al.; licensee BioMed Central Ltd.

【 图 表 】

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