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https://www.readbyqxmd.com/read/30115935/anti-tumor-efficacy-of-selinexor-kpt-330-in-gastric-cancer-is-dependent-on-nuclear-accumulation-of-p53-tumor-suppressor
#1
Vinod Vijay Subhash, Mei Shi Yeo, Lingzhi Wang, Shi Hui Tan, Foong Ying Wong, Win Lwin Thuya, Woei Loon Tan, Praveen C Peethala, Mu Yar Soe, David S P Tan, Nisha Padmanabhan, Erkan Baloglu, Sharon Shacham, Patrick Tan, H Phillip Koeffler, Wei Peng Yong
Exportin-1 (XPO1) controls the nucleo-cytoplasmic trafficking of several key growth regulatory and tumor suppressor proteins. Nuclear export blockade through XPO1 inhibition is a target for therapeutic inhibition in many cancers. Studies have suggested XPO1 upregulation as an indicator of poor prognosis in gastric cancer. In the current study, we investigated the anti-tumor efficacy of selective inhibitors of nuclear export (SINE) compounds KPT-185, KTP-276 and clinical stage selinexor (KPT-330) in gastric cancer...
August 16, 2018: Scientific Reports
https://www.readbyqxmd.com/read/30112106/selinexor-reduces-the-expression-of-dna-damage-repair-proteins-and-sensitizes-cancer-cells-to-dna-damaging-agents
#2
Trinayan Kashyap, Christian Argueta, Thaddeus Unger, Boris Klebanov, Sophia Debler, William Senapedis, Marsha L Crochiere, Margaret S Lee, Michael Kauffman, Sharon Shacham, Yosef Landesman
Introduction: The goal of this study was to examine the effects of selinexor, an inhibitor of exportin-1 mediated nuclear export, on DNA damage repair and to evaluate the cytotoxic effects of selinexor in combination with DNA damaging agents (DDAs) in cancer cells. Results: Selinexor reduced the expression of DNA damage repair (DDR) proteins. This did not induce significant DNA damage in tested cell lines. Inhibition of DDR protein expression resulted in enhanced cancer cell death when cells were pretreated with DDAs...
July 20, 2018: Oncotarget
https://www.readbyqxmd.com/read/30045709/decrease-of-5-hydroxymethylcytosine-and-tet1-with-nuclear-exclusion-of-tet2-in-small-intestinal-neuroendocrine-tumors
#3
Elham Barazeghi, Surendra Prabhawa, Olov Norlén, Per Hellman, Peter Stålberg, Gunnar Westin
BACKGROUND: Small intestinal neuroendocrine tumors (SI-NETs) originate from enterochromaffin cells scattered in the intestinal mucosa of the ileum and jejunum. Loss of one copy of chromosome 18 is the most frequent observed aberration in primary tumors and metastases. The aim of this study was to investigate possible involvement of 5-hydroxymethylcytosine (5hmC), TET1 and TET2 in SI-NETs. METHODS: The analysis was conducted using 40 primary tumors and corresponding 47 metastases...
July 25, 2018: BMC Cancer
https://www.readbyqxmd.com/read/30037299/loss-of-p53-expression-in-cancer-cells-alters-cell-cycle-response-after-inhibition-of-exportin-1-but-does-not-prevent-cell-death
#4
Joshua M Marcus, Russell T Burke, Andrea E Doak, Soyeon Park, James D Orth
The tumor suppressor protein p53 is central to the cellular stress response and may be a predictive biomarker for cancer treatments. Upon stress, wildtype p53 accumulates in the nucleus where it enforces cellular responses, including cell cycle arrest and cell death. p53 is so dominant in its effects, that p53 enforcement - or - restoration therapy is being studied for anti-cancer therapy. Two mechanistically distinct small molecules that act via p53 are the selective inhibitor of nuclear export, selinexor, and MDM2 inhibitor, nutlin-3a...
2018: Cell Cycle
https://www.readbyqxmd.com/read/30015632/leukemogenic-nucleophosmin-mutation-disrupts-the-transcription-factor-hub-that-regulates-granulomonocytic-fates
#5
Xiaorong Gu, Quteba Ebrahem, Reda Z Mahfouz, Metis Hasipek, Francis Enane, Tomas Radivoyevitch, Nicolas Rapin, Bartlomiej Przychodzen, Zhenbo Hu, Ramesh Balusu, Claudiu V Cotta, David Wald, Christian Argueta, Yosef Landesman, Maria Paola Martelli, Brunangelo Falini, Hetty Carraway, Bo T Porse, Jaroslaw Maciejewski, Babal K Jha, Yogen Saunthararajah
Nucleophosmin (NPM1) is among the most frequently mutated genes in acute myeloid leukemia (AML). It is not known, however, how the resulting oncoprotein mutant NPM1 is leukemogenic. To reveal the cellular machinery in which NPM1 participates in myeloid cells, we analyzed the endogenous NPM1 protein interactome by mass spectrometry and discovered abundant amounts of the master transcription factor driver of monocyte lineage differentiation PU.1 (also known as SPI1). Mutant NPM1, which aberrantly accumulates in cytoplasm, dislocated PU...
October 1, 2018: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/29950445/targeting-the-xpo1-dependent-nuclear-export-of-e2f7-reverses-anthracycline-resistance-in-head-and-neck-squamous-cell-carcinomas
#6
Natalia Saenz-Ponce, Rachael Pillay, Lilia Merida de Long, Trinayan Kashyap, Christian Argueta, Yosef Landesman, Mehlika Hazar-Rethinam, Samuel Boros, Benedict Panizza, Maarten Jacquemyn, Dirk Daelemans, Orla M Gannon, Nicholas A Saunders
Patient mortality rates have remained stubbornly high (40%) for the past 35 years in head and neck squamous cell carcinoma (HNSCC) due to inherent or acquired drug resistance. Thus, a critical issue in advanced SCC is to identify and target the mechanisms that contribute to therapy resistance. We report that the transcriptional inhibitor, E2F7, is mislocalized to the cytoplasm in >80% of human HNSCCs, whereas the transcriptional activator, E2F1, retains localization to the nucleus in SCC. This results in an imbalance in the control of E2F-dependent targets such as SPHK1 , which is derepressed and drives resistance to anthracyclines in HNSCC...
June 27, 2018: Science Translational Medicine
https://www.readbyqxmd.com/read/29876006/selinexor-synergizes-with-dexamethasone-to-repress-mtorc1-signaling-and-induce-multiple-myeloma-cell-death
#7
Christian Argueta, Trinayan Kashyap, Boris Klebanov, Thaddeus J Unger, Cathy Guo, Susie Harrington, Erkan Baloglu, Margaret Lee, William Senapedis, Sharon Shacham, Yosef Landesman
Multiple myeloma (MM) is a plasma cell neoplasm that results in over 11,000 deaths in the United States annually. The backbone therapy for the treatment of MM patients almost always includes combinations with corticosteroids such as dexamethasone (DEX). We found that DEX in combination with selinexor, an inhibitor of exportin-1 (XPO1) activity, synergistically inhibits the mTOR pathway and subsequently promotes cell death in MM cells. Specifically, we show that selinexor induces the expression of the glucocorticoid receptor (GR) and when combined with dexamethasone increases GR transcriptional activity...
May 22, 2018: Oncotarget
https://www.readbyqxmd.com/read/29866745/the-xpo1-inhibitor-selinexor-inhibits-translation-and-enhances-the-radiosensitivity-of-glioblastoma-cells-grown-in-vitro-and-in-vivo
#8
Amy Wahba, Barbara H Rath, John W O'Neill, Kevin Camphausen, Philip J Tofilon
Analysis of the radiation-induced translatome of glioblastoma stem-like cells (GSC) identified an interacting network in which XPO1 serves as a major hub protein. To determine whether this nuclear export protein provides a target for radiosensitization, we defined the effects of clinically relevant XPO1 inhibitor selinexor on the radiosensitivity of glioblastoma cells. As determined by clonogenic survival analysis, selinexor enhanced the radiosensitivity of GSCs but not normal fibroblast cell lines. On the basis of γH2AX foci and neutral comet analyses, selinexor inhibited the repair of radiation-induced DNA double-strand breaks in GSCs, suggesting that the selinexor-induced radiosensitization is mediated by an inhibition of DNA repair...
August 2018: Molecular Cancer Therapeutics
https://www.readbyqxmd.com/read/29773601/combinatorial-targeting-of-xpo1-and-flt3-exerts-synergistic-anti-leukemia-effects-through-induction-of-differentiation-and-apoptosis-in-flt3-mutated-acute-myeloid-leukemias-from-concept-to-clinical-trial
#9
Weiguo Zhang, Charlie Ly, Jo Ishizawa, Hong Mu, Vivian Ruvolo, Sharon Shacham, Naval Daver, Michael Andreeff
Targeted therapies against FLT3 -mutated acute myeloid leukemias have shown limited clinical efficacy primarily because of the acquisition of secondary mutations in FLT3 and persistent activation of downstream pro-survival pathways such as MEK/ERK, PI3K/AKT, and STAT5. Activation of these additional kinases may also result in phosphorylation of tumor suppressor proteins promoting their nuclear export. Thus, co-targeting nuclear export proteins (e.g., XPO1) and FLT3 concomitantly may be therapeutically effective...
October 2018: Haematologica
https://www.readbyqxmd.com/read/29707241/kpt-330-inhibition-of-chromosome-region-maintenance-1-is-cytotoxic-and-sensitizes-chronic-myeloid-leukemia-to-imatinib
#10
Danian Nie, Kezhi Huang, Songmei Yin, Yiqing Li, Shuangfeng Xie, Liping Ma, Xiuju Wang, Yudan Wu, Jie Xiao, Jieyu Wang, Wenjuan Yang, Hongyun Liu
As tyrosine kinase inhibitors (e.g., Imatinib, IM) fail to induce long-term response in some chronic myeloid leukemia (CML), novel therapies targeting leukemia-dysregulated pathways are necessary. Nuclear-cytoplasmic trafficking of proteins play a key role in the development of leukemia and drug resistance. KPT-330 (Selinexor), an inhibitor of chromosome region maintenance 1 (CRM1, nuclear receptor exportin 1, XPO1), demonstrated activities against a few hematological malignancies. We examined the anti-leukemic efficacy of KPT-330 in IM-resistant CML...
2018: Cell Death Discovery
https://www.readbyqxmd.com/read/29610030/clinical-implications-of-targeting-xpo1-mediated-nuclear-export-in-multiple-myeloma
#11
REVIEW
Ujjawal H Gandhi, William Senapedis, Erkan Baloglu, Thaddeus J Unger, Ajai Chari, Dan Vogl, Robert F Cornell
Multiple myeloma (MM) is a malignancy of plasma cells that is typically chronic, and relapse is common. Current therapeutic strategies include combination and sequential treatments with corticosteroids, alkylating agents, proteasomal inhibitors, immunomodulators, and monoclonal antibodies. These drugs prolong survival but ultimately become ineffective. Exportin 1 (XPO1), a nuclear export protein, is overexpressed in MM cells, and knockdown studies have suggested that XPO1 is essential for MM cell survival. Selective inhibitor of nuclear export (SINE) compounds are novel, orally bioavailable class of agents that specifically inhibit XPO1...
May 2018: Clinical Lymphoma, Myeloma & Leukemia
https://www.readbyqxmd.com/read/29487219/a-phase-ii-trial-of-selinexor-an-oral-selective-inhibitor-of-nuclear-export-compound-in-abiraterone-and-or-enzalutamide-refractory-metastatic-castration-resistant-prostate-cancer
#12
Xiao X Wei, Adam P Siegel, Rahul Aggarwal, Amy M Lin, Terence W Friedlander, Lawrence Fong, Won Kim, Mirela Louttit, Emily Chang, Li Zhang, Charles J Ryan
LESSONS LEARNED: In abiraterone- and/or enzalutamide-refractory metastatic castration-resistant prostate cancer (mCRPC) patients, selinexor led to prostate-specific antigen and/or radiographic responses in a subset of patients, indicating clinical activity in this indication.Despite twice-a-week dosing and maximal symptomatic management, selinexor was associated with significant anorexia, nausea, and fatigue in mCRPC patients refractory to second-generation anti-androgen therapies, limiting further clinical development in this patient population...
June 2018: Oncologist
https://www.readbyqxmd.com/read/29429914/selinexor-and-dexamethasone-in-multiple-myeloma
#13
Talha Khan Burki
No abstract text is available yet for this article.
March 2018: Lancet Oncology
https://www.readbyqxmd.com/read/29381435/selective-inhibition-of-nuclear-export-with-oral-selinexor-for-treatment-of-relapsed-or-refractory-multiple-myeloma
#14
Dan T Vogl, David Dingli, Robert Frank Cornell, Carol Ann Huff, Sundar Jagannath, Divaya Bhutani, Jeffrey Zonder, Rachid Baz, Ajay Nooka, Joshua Richter, Craig Cole, Ravi Vij, Andrzej Jakubowiak, Rafat Abonour, Gary Schiller, Terri L Parker, Luciano J Costa, David Kaminetzky, James E Hoffman, Andrew J Yee, Ajai Chari, David Siegel, Rafael Fonseca, Scott Van Wier, Gregory Ahmann, Ilsel Lopez, Michael Kauffman, Sharon Shacham, Jean-Richard Saint-Martin, Carla D Picklesimer, Cassandra Choe-Juliak, A Keith Stewart
Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease)...
March 20, 2018: Journal of Clinical Oncology: Official Journal of the American Society of Clinical Oncology
https://www.readbyqxmd.com/read/29340049/pharmacological-treatment-with-inhibitors-of-nuclear-export-enhances-the-antitumor-activity-of-docetaxel-in-human-prostate-cancer
#15
Giovanni Luca Gravina, Andrea Mancini, Alessandro Colapietro, Francesco Marampon, Roberta Sferra, Simona Pompili, Leda Assunta Biordi, Roberto Iorio, Vincenzo Flati, Christian Argueta, Yosef Landesman, Michael Kauffman, Sharon Shacham, Claudio Festuccia
Background and aims: Docetaxel (DTX) modestly increases patient survival of metastatic castration-resistant prostate cancer (mCRPC) due to insurgence of pharmacological resistance. Deregulation of Chromosome Region Maintenance (CRM-1)/ exportin-1 (XPO-1)-mediated nuclear export may play a crucial role in this phenomenon. Material and methods: Here, we evaluated the effects of two Selective Inhibitor of Nuclear Export (SINE) compounds, selinexor (KPT-330) and KPT-251, in association with DTX by using 22rv1, PC3 and DU145 cell lines with their...
December 19, 2017: Oncotarget
https://www.readbyqxmd.com/read/29304833/a-phase-i-study-of-selinexor-in-combination-with-high-dose-cytarabine-and-mitoxantrone-for-remission-induction-in-patients-with-acute-myeloid-leukemia
#16
Amy Y Wang, Howard Weiner, Margaret Green, Hua Chang, Noreen Fulton, Richard A Larson, Olatoyosi Odenike, Andrew S Artz, Michael R Bishop, Lucy A Godley, Michael J Thirman, Satyajit Kosuri, Jane E Churpek, Emily Curran, Kristen Pettit, Wendy Stock, Hongtao Liu
BACKGROUND: Novel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents. METHODS: We report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito)...
January 5, 2018: Journal of Hematology & Oncology
https://www.readbyqxmd.com/read/29299164/xpo1-target-occupancy-measurements-confirm-the-selinexor-recommended-phase-2-dose
#17
Marsha L Crochiere, Stefan Hannus, Kerrin Hansen, Frank Becker, Erkan Baloglu, Margaret Lee, Michael Kauffman, Sharon Shacham, Yosef Landesman
XPO1 (exportin 1) is the main nuclear export protein with over 200 different protein cargos. XPO1 is overexpressed in tumor cells and high levels are correlated with poor prognosis. Selective Inhibitor of Nuclear Export (SINE) compounds block nuclear export by inhibiting XPO1. The first SINE compound, selinexor, shows promising anti-cancer activity across hematological and solid tumors in Phase 2 and 3 clinical trials. The 2nd generation SINE compound KPT-8602 is being evaluated as an anti-cancer agent in a Phase 1 clinical trial...
December 15, 2017: Oncotarget
https://www.readbyqxmd.com/read/29242296/promising-activity-of-selinexor-in-the-treatment-of-a-patient-with-refractory-diffuse-large-b-cell-lymphoma-and-central-nervous-system-involvement
#18
LETTER
Sabela Bobillo, Pau Abrisqueta, Cecilia Carpio, Priyanka Raheja, Josep Castellví, Marta Crespo, Francesc Bosch
No abstract text is available yet for this article.
February 2018: Haematologica
https://www.readbyqxmd.com/read/29203585/safety-and-efficacy-of-selinexor-in-relapsed-or-refractory-multiple-myeloma-and-waldenstrom-macroglobulinemia
#19
Christine Chen, David Siegel, Martin Gutierrez, Meagan Jacoby, Craig C Hofmeister, Nashat Gabrail, Rachid Baz, Morten Mau-Sorensen, Jesus G Berdeja, Michael Savona, Lynn Savoie, Suzanne Trudel, Nuchanan Areethamsirikul, T J Unger, Tami Rashal, Tim Hanke, Michael Kauffman, Sharon Shacham, Donna Reece
Novel therapies are needed for patients with relapsed or refractory multiple myeloma (MM). We conducted a multicenter, phase 1 study in advanced hematological malignancies to assess the safety, efficacy, and recommended phase 2 dose (RP2D) of oral selinexor, a selective inhibitor of the nuclear export protein XPO1. In the dose-escalation phase, 25 patients with heavily pretreated MM (22) or Waldenstrom macroglobulinemia (3) were administered selinexor (3-60 mg/m2 ) in 8 or 10 doses per 28-day cycle. In the dose-expansion phase, 59 patients with MM received selinexor at 45 or 60 mg/m2 with 20 mg dexamethasone, twice weekly in 28-day cycles, or selinexor (40 or 60 mg flat dose) without corticosteroids in 21-day cycles...
February 22, 2018: Blood
https://www.readbyqxmd.com/read/29155058/foxo-1-contributes-to-the-efficacy-of-the-combination-of-the-xpo1-inhibitor-selinexor-and-cisplatin-in-ovarian-carcinoma-preclinical-models
#20
Cristina Corno, Simone Stucchi, Michelandrea De Cesare, Nives Carenini, Serena Stamatakos, Emilio Ciusani, Lucia Minoli, Eugenio Scanziani, Christian Argueta, Yosef Landesman, Nadia Zaffaroni, Laura Gatti, Paola Perego
The XPO1/CRM1 inhibitor selinexor (KPT-330), is currently being evaluated in multiple clinical trials as an anticancer agent. XPO1 participates in the nuclear export of FoxO-1, which we previously found to be decreased in platinum-resistant ovarian carcinoma. The aim of this study was to determine whether enriching FoxO-1 nuclear localization using selinexor would increase ovarian cancer cell sensitivity to cisplatin. Selinexor, as a single agent, displayed a striking antiproliferative effect in different ovarian carcinoma cell lines...
January 2018: Biochemical Pharmacology
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