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Ref Type Journal Article
PMID (27649553)
Authors Chen Y, Camacho SC, Silvers TR, Razak AR, Gabrail NY, Gerecitano JF, Kalir E, Pereira E, Evans BR, Ramus SJ, Huang F, Priedigkeit N, Rodriguez E, Donovan M, Khan F, Kalir T, Sebra R, Uzilov A, Chen R, Sinha R, Halpert R, Billaud JN, Shacham S, McCauley D, Landesman Y, Rashal T, Kauffman M, Mirza MR, Mau-Sørensen M, Dottino P, Martignetti JA
Title Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer.
Journal Clinical cancer research : an official journal of the American Association for Cancer Research
Vol 23
Issue 6
Date 2017 Mar 15
URL
Abstract Text Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer.Experimental Design: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor.Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor-mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexor-treated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all.Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer. Clin Cancer Res; 23(6); 1552-63. ©2016 AACR.

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Molecular Profile Treatment Approach
Gene Name Source Synonyms Protein Domains Gene Description Gene Role
Therapy Name Drugs Efficacy Evidence Clinical Trials
Drug Name Trade Name Synonyms Drug Classes Drug Description
Gene Variant Impact Protein Effect Variant Description Associated with drug Resistance
Molecular Profile Indication/Tumor Type Response Type Therapy Name Approval Status Evidence Type Efficacy Evidence References
Unknown unknown ovarian cancer not applicable Cisplatin + KPT-185 Preclinical - Patient cell culture Actionable In a preclinical study, the combination of KPT-185 and Platinol (cisplatin) worked synergistically to decrease viability of platinum-resistant and platinum-sensitive immortalized and patient-derived human ovarian cancer cell lines in culture (PMID: 27649553). 27649553
Unknown unknown ovarian cancer not applicable KPT-185 Preclinical - Patient cell culture Actionable In a preclinical study, KPT-185 inhibited growth of platinum-sensitive and platinum-resistant immortalized human ovarian cancer cell lines and patient-derived ovarian cancer cell lines in culture (PMID: 27649553). 27649553
Unknown unknown ovarian cancer not applicable Selinexor Phase I Actionable In a Phase I clinical trial, Selinexor (KPT-330) treatment resulted in inhibition of tumor growth in 3/5 patients with platinum-refractory ovarian cancer, with one patient achieving a partial response and two patients achieving stable disease (PMID: 27649553). 27649553
Unknown unknown ovarian cancer not applicable Cisplatin + Selinexor Preclinical - Pdx Actionable In a preclinical study, the combination of Platinol (cisplatin) and Selinexor (KPT-330) induced tumor regression and improved survival over either agent alone in patient-derived xenograft (PDX) models of ovarian cancer, including Platinol (cisplatin)-resistant models (PMID: 27649553). 27649553