Clinical translation of nuclear export inhibitors in cancer

Senapedis, William; Baloglu, Erkan; Landesman, Yosef

doi:10.1016/j.semcancer.2014.04.005

Cited by 113 publications

(135 citation statements)

References 172 publications

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“…Driven in part by the current understanding that nuclear-cytoplasmic export is primarily driven by XPO1, a number of potential therapeutic agents targeting XPO1 have been developed and tested, and the smallmolecule SINE has shown the most promising clinical efficacy and safety (3)(4)(5)(6)51). The XPO1 inhibitor KPT-330 (selinexor) is the only compound currently being evaluated in clinical trials in solid tumors and hematologic malignancies.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

Chen

Camacho

Silvers

et al. 2017

Clinical Cancer Research

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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 selinexortreated 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.

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Section: Discussionmentioning

confidence: 99%

Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

Chen

Camacho

Silvers

et al. 2017

Clinical Cancer Research

Self Cite

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“…XPO1 is a member of the karyopherin-β family of proteins and plays a central role in nuclear export through forming complexes with Ran-GTP and with cargo proteins containing a leucine-rich nuclear export sequence (NES) [55, 56]. Selinexor inhibits the export activities of XPO1 by forming a covalent adduct with cysteine-528 of XPO1 [57–59] that functionally inactivates XPO1 and targets it for proteasomal degradation [58].…”

Section: Introductionmentioning

confidence: 99%

Identifying novel therapeutic agents using xenograft models of pediatric cancer

Kurmasheva

Houghton

2016

Cancer Chemother Pharmacol

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In the USA, the overall cure rate for all childhood cancers is seventy percent, and in many patients that ultimately fail curative therapy, initial responses to current multimodality treatments (surgery, radiation therapy and chemotherapy) is good, with overall 5-year event-free survival approaching 80 %. However, current approaches to curative therapy result in significant morbidity and long-term sequelae, including cardiac dysfunction and cognitive impairment. Furthermore, dose-intensive chemotherapy with conventional agents has not significantly improved outcomes for patients that present with advanced or meta-static disease. Classical cytotoxic agents remain the backbone for curative therapy of both hematologic and solid tumors of childhood. While ‘molecularly’ targeted agents have shown some clinical activity, responses are often modest and of short duration; hence, there is a need to identify new classes of cytotoxic agent that are effective in patients at relapse and that have reduced or different toxicity profiles to normal tissues. Here we review the pediatric pre-clinical testing program experience of testing novel agents, and the value and limitations of preclinical xenograft models and genetically engineered mouse models for developing novel agents for treatment of childhood cancer.

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“…This cell dies in late S- or G2-phase after 21 hours 30 min; a normal cell cycle is approximately 15 hours. The effects of selinexor are being studied for different blood and solid tumors 35 .…”

Section: Representative Resultsmentioning

confidence: 99%

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

Burke

Orth

2016

JoVE

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The response of single cells to anti-cancer drugs contributes significantly in determining the population response, and therefore is a major contributing factor in the overall outcome. Immunoblotting, flow cytometry and fixed cell experiments are often used to study how cells respond to anti-cancer drugs. These methods are important, but they have several shortcomings. Variability in drug responses between cancer and normal cells, and between cells of different cancer origin, and transient and rare responses are difficult to understand using population averaging assays and without being able to directly track and analyze them longitudinally. The microscope is particularly well suited to image live cells. Advancements in technology enable us to routinely image cells at a resolution that enables not only cell tracking, but also the observation of a variety of cellular responses. We describe an approach in detail that allows for the continuous time-lapse imaging of cells during the drug response for essentially as long as desired, typically up to 96 hours. Using variations of the approach, cells can be monitored for weeks. With the employment of genetically encoded fluorescent biosensors numerous processes, pathways and responses can be followed. We show examples that include tracking and quantification of cell growth and cell cycle progression, chromosome dynamics, DNA damage, and cell death. We also discuss variations of the technique and its flexibility, and highlight some common pitfalls.

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Clinical translation of nuclear export inhibitors in cancer

Cited by 113 publications

References 172 publications

Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

Inhibition of the Nuclear Export Receptor XPO1 as a Therapeutic Target for Platinum-Resistant Ovarian Cancer

Identifying novel therapeutic agents using xenograft models of pediatric cancer

Through the Looking Glass: Time-lapse Microscopy and Longitudinal Tracking of Single Cells to Study Anti-cancer Therapeutics

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