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https://www.readbyqxmd.com/read/27863053/caffeic-acid-phenethyl-ester-cape-revisited-covalent-modulation-of-xpo1-crm1-activities-and-implication-for-its-mechanism-of-action
#1
Sijin Wu, Keren Zhang, Hongqiang Qin, Mingshan Niu, Weijie Zhao, Mingliang Ye, Hanfa Zou, Yongliang Yang
Caffeic acid phenethyl ester (CAPE) is the bioactive constituent of propolis from honeybee hives and is well known for its anti-inflammatory, anti-carcinogenic, antioxidant and immunomodulatory properties. Herein, we revisited the cellular mechanism underlying the diverse biological effects of CAPE. We demonstrated that XPO1/CRM1, a major nuclear export receptor, is a cellular target of CAPE. Through nuclear export functional assay, we observed a clear shift of XPO1 cargo proteins from a cytoplasmic localization to nucleus when treated with CAPE...
November 8, 2016: Chemical Biology & Drug Design
https://www.readbyqxmd.com/read/27825468/novel-therapeutic-targets-in-waldenstrom-macroglobulinemia
#2
REVIEW
Aneel Paulus, Sikander Ailawadhi, Asher Chanan-Khan
Understanding of molecular mechanisms that drive Waldenstrom macroglobulinemia (WM) cell survival are rapidly evolving. This review briefly highlights emerging "WM-relevant" targets; for which therapeutic strategies are currently being investigated in preclinical and clinical studies. With the discovery of MYD88L265P signaling and remarkable activity of ibrutinib in WM, other targets within the B-cell receptor pathway are now being focused on for therapeutic intervention. Additional targets which play a role in WM cell survival include TLR7, 8 and 9, proteasome-associated deubiquitinating enzymes (USP14 and UCHL5), XPO1/CRM1 and AURKA...
June 2016: Best Practice & Research. Clinical Haematology
https://www.readbyqxmd.com/read/27807105/xpo1-may-be-therapeutically-targetable-in-kras-mutant-nsclc
#3
(no author information available yet)
XPO1 inhibition selectively targets KRAS-mutant NSCLC cells by suppressing NFκB signaling.
November 2016: Cancer Discovery
https://www.readbyqxmd.com/read/27806331/xpo1-inhibitor-combination-therapy-with-bortezomib-or-carfilzomib-induces-nuclear-localization-of-i%C3%AE%C2%BAb%C3%AE-and-overcomes-acquired-proteasome-inhibitor-resistance-in-human-multiple-myeloma
#4
Joel G Turner, Trinayan Kashyap, Jana L Dawson, Juan Gomez, Alexis A Bauer, Steven Grant, Yun Dai, Kenneth H Shain, Mark Meads, Yosef Landesman, Daniel M Sullivan
Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired resistance in MM. PI-resistant myeloma cell lines both in vitro and in vivo and refractory myeloma patient biopsies were treated with selinexor/bortezomib or carfilzomib and assayed for apoptosis. Mechanistic studies included NFκB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assays...
October 28, 2016: Oncotarget
https://www.readbyqxmd.com/read/27780859/the-second-generation-exportin-1-inhibitor-kpt-8602-demonstrates-potent-activity-against-acute-lymphoblastic-leukemia
#5
Thomas Vercruysse, Jolien De Bie, Jasper Neggers, Maarten Jacquemyn, Els Vanstreels, Jonathan Leo Schmid-Burgk, Veit Hornung, Erkan Baloglu, Yosef Landesman, William Senapedis, Sharon Shacham, Antonis Dagklis, Jan Cools, Dirk Daelemans
PURPOSE: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports many cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibition of XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in Phase-II/IIb clinical trials when dosed 1 - 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily...
October 25, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27757501/-radiation-response-enhanced-by-inhibition-of-xpo1-in-preclinical-rectal-cancer-models
#6
Moritz von Fallois, Reinhard Depping
No abstract text is available yet for this article.
October 18, 2016: Strahlentherapie und Onkologie: Organ der Deutschen Röntgengesellschaft ... [et Al]
https://www.readbyqxmd.com/read/27733172/crm1-xpo1-is-associated-with-clinical-outcome-in-glioma-and-represents-a-therapeutic-target-by-perturbing-multiple-core-pathways
#7
Xuejiao Liu, Yulong Chong, Yiming Tu, Ning Liu, Chenglong Yue, Zhenglei Qi, Huize Liu, Yao Yao, Hongmei Liu, Shangfeng Gao, Mingshan Niu, Rutong Yu
BACKGROUND: Malignant gliomas are associated with a high mortality rate, and effective treatment options are limited. Thus, the development of novel targeted treatments to battle this deadly disease is imperative. METHODS: In this study, we investigated the in vitro effects of the novel reversible chromosomal region maintenance 1 (CRM1) inhibitor S109 on cell proliferation in human gliomas. S109 was also evaluated in an intracranial glioblastoma xenograft model...
October 12, 2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27713151/selinexor-a-selective-inhibitor-of-nuclear-export-sine-compound-acts-through-nf-%C3%AE%C2%BAb-deactivation-and-combines-with-proteasome-inhibitors-to-synergistically-induce-tumor-cell-death
#8
Trinayan Kashyap, Christian Argueta, Amro Aboukameel, Thaddeus John Unger, Boris Klebanov, Ramzi M Mohammad, Irfana Muqbil, Asfar S Azmi, Claire Drolen, William Senapedis, Margaret Lee, Michael Kauffman, Sharon Shacham, Yosef Landesman
The nuclear export protein, exportin-1 (XPO1/CRM1), is overexpressed in many cancers and correlates with poor prognosis. Selinexor, a first-in-class Selective Inhibitor of Nuclear Export (SINE) compound, binds covalently to XPO1 and blocks its function. Treatment of cancer cells with selinexor results in nuclear retention of major tumor suppressor proteins and cell cycle regulators, leading to growth arrest and apoptosis. Recently, we described the selection of SINE compound resistant cells and reported elevated expression of inflammation-related genes in these cells...
October 4, 2016: Oncotarget
https://www.readbyqxmd.com/read/27699255/identifying-candidate-genes-for-2p15p16-1-microdeletion-syndrome-using-clinical-genomic-and-functional-analysis
#9
Hani Bagheri, Chansonette Badduke, Ying Qiao, Rita Colnaghi, Iga Abramowicz, Diana Alcantara, Christopher Dunham, Jiadi Wen, Robert S Wildin, Malgorzata J M Nowaczyk, Jennifer Eichmeyer, Anna Lehman, Bruno Maranda, Sally Martell, Xianghong Shan, Suzanne M E Lewis, Mark O'Driscoll, Cheryl Y Gregory-Evans, Evica Rajcan-Separovic
The 2p15p16.1 microdeletion syndrome has a core phenotype consisting of intellectual disability, microcephaly, hypotonia, delayed growth, common craniofacial features, and digital anomalies. So far, more than 20 cases of 2p15p16.1 microdeletion syndrome have been reported in the literature; however, the size of the deletions and their breakpoints vary, making it difficult to identify the candidate genes. Recent reports pointed to 4 genes (XPO1, USP34, BCL11A, and REL) that were included, alone or in combination, in the smallest deletions causing the syndrome...
March 17, 2016: JCI Insight
https://www.readbyqxmd.com/read/27693556/anti-tumor-activity-of-selective-inhibitor-of-nuclear-export-sine-compounds-is-enhanced-in-non-hodgkin-lymphoma-through-combination-with-mtor-inhibitor-and-dexamethasone
#10
Irfana Muqbil, Amro Aboukameel, Sivan Elloul, Robert Carlson, William Senapedis, Erkan Baloglu, Michael Kauffman, Sharon Shacham, Divaya Bhutani, Jeffrey Zonder, Asfar S Azmi, Ramzi M Mohammad
In previous studies we demonstrated that targeting the nuclear exporter protein exportin-1 (CRM1/XPO1) by a selective inhibitor of nuclear export (SINE) compound is a viable therapeutic strategy against Non-Hodgkin Lymphoma (NHL). Our studies along with pre-clinical work from others led to the evaluation of the lead SINE compound, selinexor, in a phase 1 trial in patients with CLL or NHL (NCT02303392). Continuing our previous work, we studied combinations of selinexor-dexamethasone (DEX) and selinexor-everolimus (EVER) in NHL...
September 28, 2016: Cancer Letters
https://www.readbyqxmd.com/read/27680702/xpo1-dependent-nuclear-export-is-a-druggable-vulnerability-in-kras-mutant-lung-cancer
#11
Jimi Kim, Elizabeth McMillan, Hyun Seok Kim, Niranjan Venkateswaran, Gurbani Makkar, Jaime Rodriguez-Canales, Pamela Villalobos, Jasper Edgar Neggers, Saurabh Mendiratta, Shuguang Wei, Yosef Landesman, William Senapedis, Erkan Baloglu, Chi-Wan B Chow, Robin E Frink, Boning Gao, Michael Roth, John D Minna, Dirk Daelemans, Ignacio I Wistuba, Bruce A Posner, Pier Paolo Scaglioni, Michael A White
The common participation of oncogenic KRAS proteins in many of the most lethal human cancers, together with the ease of detecting somatic KRAS mutant alleles in patient samples, has spurred persistent and intensive efforts to develop drugs that inhibit KRAS activity. However, advances have been hindered by the pervasive inter- and intra-lineage diversity in the targetable mechanisms that underlie KRAS-driven cancers, limited pharmacological accessibility of many candidate synthetic-lethal interactions and the swift emergence of unanticipated resistance mechanisms to otherwise effective targeted therapies...
September 28, 2016: Nature
https://www.readbyqxmd.com/read/27649553/inhibition-of-the-nuclear-export-receptor-xpo1-as-a-therapeutic-target-for-platinum-resistant-ovarian-cancer
#12
John A Martignetti, Ying Chen, Catalina Camacho, Thomas R Silvers, Albiruni R A Razak, Nashat Y Gabrail, John F Gerecitano, Eva Kalir, Elena Pereira, Brad R Evans, Susan J Ramus, Fei Huang, Nolan Priedigkeit, Estefania Rodriguez, Michael Donovan, Faisal M Khan, Tamara Kalir, Robert P Sebra, Andrew Uzilov, Rong Chen, Rileen Sinha, Richard Halpert, Jean-Noel Billaud, Sharon Shacham, Dilara McCauley, Yosef Landesman, Tami Rashal, Michael Kauffman, Mansoor R Mirza, Morten Mau-Sørensen, Peter Dottino
PURPOSE: Ovarian cancer's (OvCa) high fatality-to-case ratio 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 OvCa. EXPERIMENTAL DESIGN: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO data sets and tissue microarrays (TMAs)...
September 20, 2016: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
https://www.readbyqxmd.com/read/27634897/heterozygous-mutation-of-cysteine528-in-xpo1-is-sufficient-for-resistance-to-selective-inhibitors-of-nuclear-export
#13
Jasper Edgar Neggers, Els Vanstreels, Erkan Baloglu, Sharon Shacham, Yosef Landesman, Dirk Daelemans
Exportin-1 (CRM1/XPO1) is a crucial nuclear export protein that transports a wide variety of proteins from the nucleus to the cytoplasm. These cargo proteins include tumor suppressors and growth-regulatory factors and as such XPO1 is considered a potential anti-cancer target. From this perspective, inhibition of the XPO1-mediated nuclear export by selective inhibitor of nuclear export (SINE) compounds has shown broad-spectrum anti-cancer activity. Furthermore, the clinical candidate SINE, selinexor, is currently in multiple phase I/II/IIb trials for treatment of cancer...
September 13, 2016: Oncotarget
https://www.readbyqxmd.com/read/27557643/treatment-of-acquired-drug-resistance-in-multiple-myeloma-by-combination-therapy-with-xpo1-and-topoisomerase-ii-inhibitors
#14
Joel G Turner, Jana L Dawson, Steven Grant, Kenneth H Shain, William S Dalton, Yun Dai, Mark Meads, Rachid Baz, Michael Kauffman, Sharon Shacham, Daniel M Sullivan
BACKGROUND: Acquired drug resistance is the greatest obstacle to the successful treatment of multiple myeloma (MM). Despite recent advanced treatment options such as liposomal formulations, proteasome inhibitors, immunomodulatory drugs, myeloma-targeted antibodies, and histone deacetylase inhibitors, MM is still considered an incurable disease. METHODS: We investigated whether the clinical exportin 1 (XPO1) inhibitor selinexor (KPT-330), when combined with pegylated liposomal doxorubicin (PLD) or doxorubicin hydrochloride, could overcome acquired drug resistance in multidrug-resistant human MM xenograft tumors, four different multidrug-resistant MM cell lines, or ex vivo MM biopsies from relapsed/refractory patients...
2016: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/27548513/cover-image-volume-231-number-12-december-2016
#15
Cheryl Taylor-Kashton, Daniel Lichtensztejn, Erkan Baloglu, William Senapedis, Sharon Shacham, Michael G Kauffman, Rami Kotb, Sabine Mai
Cover: The cover image, by Sabine Mai et al., is based on the Research Article XPO1 Inhibition Preferentially Disrupts the 3D Nuclear Organization of Telomeres in Tumor Cells, DOI: 10.1002/jcp.25378.
December 2016: Journal of Cellular Physiology
https://www.readbyqxmd.com/read/27533791/er%C3%AE-xpo1-cross-talk-controls-tamoxifen-sensitivity-in-tumors-by-altering-erk5-cellular-localization
#16
Kinga Wrobel, Yiru Chen Zhao, Eylem Kulkoyluoglu, Karen Lee Ann Chen, Kadriye Hieronymi, Jamie Holloway, Sarah Li, Tania Ray, Partha Sarathi Ray, Yosef Landesman, Alexander Edward Lipka, Rebecca Lee Smith, Zeynep Madak-Erdogan
Most breast cancer deaths occur in women with recurrent, estrogen receptor (ER)-α(+), metastatic tumors. There is a critical need for therapeutic approaches that include novel, targetable mechanism-based strategies by which ERα (+) tumors can be resensitized to endocrine therapies. The objective of this study was to validate a group of nuclear transport genes as potential biomarkers to predict the risk of endocrine therapy failure and to evaluate the inhibition of XPO1, one of these genes as a novel means to enhance the effectiveness of endocrine therapies...
October 2016: Molecular Endocrinology
https://www.readbyqxmd.com/read/27507877/phase-i-study-of-selinexor-a-selective-inhibitor-of-nuclear-export-in-combination-with-fludarabine-and-cytarabine-in-pediatric-relapsed-or-refractory-acute-leukemia
#17
Thomas B Alexander, Norman J Lacayo, John K Choi, Raul C Ribeiro, Ching-Hon Pui, Jeffrey E Rubnitz
Purpose To characterize the toxicity, pharmacokinetics, and pharmacodynamics of selinexor, a selective inhibitor of nuclear export, when combined with fludarabine and cytarabine, in children with relapsed or refractory leukemia. Patients and Methods Eighteen patients with relapsed or refractory acute leukemia were enrolled in the SELHEM (Selinexor With Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome) clinical trial (NCT02212561). Selinexor, initially at 30 mg/m(2) per dose, was given orally on days 1, 3, 8, 10, 22, and 24 and was escalated according to a rolling-six design...
December 2016: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/27487856/xpo1-therapeutic-%C3%A2-and-prognostic-target-in-sarcomas
#18
COMMENT
François Bertucci, Pascal Finetti, Daniel Birnbaum
No abstract text is available yet for this article.
2016: Oncoscience
https://www.readbyqxmd.com/read/27479820/detection-and-prognostic-value-of-recurrent-exportin-1-mutations-in-tumor-and-cell-free-circulating-dna-of-patients-with-classical-hodgkin-lymphoma
#19
Vincent Camus, Aspasia Stamatoullas, Sylvain Mareschal, Pierre-Julien Viailly, Nasrin Sarafan-Vasseur, Elodie Bohers, Sydney Dubois, Jean Michel Picquenot, Philippe Ruminy, Catherine Maingonnat, Philippe Bertrand, Marie Cornic, Valérie Tallon-Simon, Stéphanie Becker, Liana Veresezan, Thierry Frebourg, Pierre Vera, Christian Bastard, Hervé Tilly, Fabrice Jardin
Classical Hodgkin lymphoma is one of the most common lymphomas and shares clinical and genetic features with primary mediastinal B-cell lymphoma. In this retrospective study, we analyzed the recurrent hotspot mutation of the exportin 1 (XPO1, p.E571K) gene, previously identified in primary mediastinal B-cell lymphoma, in biopsies and plasma circulating cell-free DNA from patients with classical Hodgkin lymphoma using a highly sensitive digital PCR technique. A total of 94 patients were included in the present study...
September 2016: Haematologica
https://www.readbyqxmd.com/read/27469216/genomic-characterization-of-high-count-mbl-cases-indicates-that-early-detection-of-driver-mutations-and-subclonal-expansion-are-predictors-of-adverse-clinical-outcome
#20
S Barrio, T D Shanafelt, J Ojha, K G Chaffee, C Secreto, K M Kortüm, S Pathangey, D L Van-Dyke, S L Slager, R Fonseca, N E Kay, E Braggio
High-count monoclonal B-cell lymphocytosis (MBL) is an asymptomatic expansion of clonal B cells in the peripheral blood without other manifestations of chronic lymphocytic leukemia (CLL). Yearly, 1% of MBLs evolve to CLL requiring therapy; thus being critical to understand the biological events that determine which MBLs progress to intermediate/advanced CLL. In this study, we performed targeted deep sequencing on 48 high-count MBLs, 47 of them with 2-4 sequential samples analyzed, exploring the mutation status of 21 driver genes and evaluating clonal evolution...
July 29, 2016: Leukemia: Official Journal of the Leukemia Society of America, Leukemia Research Fund, U.K
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