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|Ref Type||Journal Article|
|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|
|Date||2017 Mar 15|
|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.|
|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|