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David A Jans, Alexander J Martin, Kylie M Wagstaff
Central to eukaryotic cell function, transport into and out of the nucleus is largely mediated by members of the Importin (IMP) superfamily of transporters of α- and β-types. The first inhibitor of nuclear transport, leptomycin B (LMB), was shown to be a specific inhibitor of the IMPβ homologue Exportin 1 (EXP1) almost 20 years ago, but it has only been in the last five or so years that new inhibitors of nuclear export as well as import have been identified and characterised. Of utility in biological research, these inhibitors include those that target-specific EXPs/IMPs, with accompanying toxicity profiles, as well as agents that specifically target particular nuclear import cargoes...
February 28, 2019: Current Opinion in Cell Biology
Daniel A Luedtke, Yongwei Su, Shuang Liu, Holly Edwards, Yue Wang, Hai Lin, Jeffrey W Taub, Yubin Ge
The antiapoptotic Bcl-2 family proteins play critical roles in resistance to chemotherapy in acute myeloid leukaemia (AML). The Bcl-2-selective inhibitor ABT-199 (Venetoclax) shows promising antileukaemic activity against AML, though Mcl-1 limits its antileukaemic activity. XPO1 is a nuclear exporter overexpressed in AML cells and its inhibition decreases Mcl-1 levels in cancer cells. Thus, we hypothesized that the XPO1-selective inhibitor KPT-330 (Selinexor) can synergize with ABT-199 to induce apoptosis in AML cells through down-regulation of Mcl-1...
December 2018: Journal of Cellular and Molecular Medicine
Dongqing Yan, Anthony D Pomicter, Srinivas Tantravahi, Clinton C Mason, Anna V Senina, Jonathan M Ahmann, Qiang Wang, Hein Than, Ami B Patel, William L Heaton, Anna M Eiring, Phillip M Clair, Kevin C Gantz, Hannah M Redwine, Sabina I Swierczek, Brayden J Halverson, Erkan Baloglu, Sharon Shacham, Jamshid S Khorashad, Todd W Kelley, Mohamed E Salama, Rodney R Miles, Kenneth M Boucher, Josef T Prchal, Thomas O'Hare, Michael W Deininger
Purpose: Myelofibrosis is a hematopoietic stem cell neoplasm characterized by bone marrow reticulin fibrosis, extramedullary hematopoiesis, and frequent transformation to acute myeloid leukemia. Constitutive activation of JAK/STAT signaling through mutations in JAK2, CALR , or MPL is central to myelofibrosis pathogenesis. JAK inhibitors such as ruxolitinib reduce symptoms and improve quality of life, but are not curative and do not prevent leukemic transformation, defining a need to identify better therapeutic targets in myelofibrosis...
December 18, 2018: Clinical Cancer Research: An Official Journal of the American Association for Cancer Research
Juan Martin-Liberal, Ezequiel Pérez, Xavier García Del Muro
Soft-tissue sarcomas (STS) are a heterogeneous group of diseases that are characterized by a historic lack of active treatment options. However, several new drugs and indications have become available in recent years. Areas covered: This article reviews the most relevant phase II studies that utilize chemotherapy agents (aldoxorubicin, amrubicin, trabectedin alone or in combination with doxorubicin, and gemcitabine plus docetaxel), targeted therapies (Imatinib, dasatinib, regorafenib, tivozanib, palbociclib and selinexor), a combination of chemotherapy plus targeted therapies (fucusing on doxorubicin plus olaratumab) and immunotherapies (pembrolizumab, combination of nivolumab plus ipilimumab and adaptive cell therapy) in STS (other than gastrointestinal stromal tumors) (GIST) published from 2015...
January 2019: Expert Opinion on Investigational Drugs
Mei Ming, Wenjun Wu, Bingqing Xie, Madina Sukhanova, Weige Wang, Sabah Kadri, Shruti Sharma, Jimmy Lee, Sharon Shacham, Yosef Landesman, Natalia Maltsev, Pin Lu, Y Lynn Wang
Inhibition of B-cell receptor (BCR) signaling through the BTK inhibitor, ibrutinib, has generated a remarkable response in mantle cell lymphoma (MCL). However, approximately one third of patients do not respond well to the drug, and disease relapse on ibrutinib is nearly universal. Alternative therapeutic strategies aimed to prevent and overcome ibrutinib resistance are needed. We compared and contrasted the effects of selinexor, a selective inhibitor of nuclear export, with ibrutinib in six MCL cell lines that display differential intrinsic sensitivity to ibrutinib...
December 2018: Molecular Cancer Therapeutics
Amro Aboukameel, Irfana Muqbil, Erkan Baloglu, William Senapedis, Yosef Landesman, Christian Argueta, Michael Kauffman, Hua Chang, Trinayan Kashyap, Sharon Shacham, Jasper E Neggers, Dirk Daelemans, Elisabeth I Heath, Asfar S Azmi
Emerging studies have shown that the expression of AR splice variants (ARv) lacking ligand-binding domain is associated with castrate-resistant prostate cancer (CRPC) and higher risk of tumor metastasis and recurrence. Nuclear export protein XPO1 regulates the nuclear localization of many proteins including tumor suppressor proteins. Increased XPO1 in prostate cancer is associated with a high Gleason score and bone metastasis. In this study, we found that high expression of AR splice variant 7 (AR-v7) was correlated with increased XPO1 expression...
October 19, 2018: Oncotarget
Chetasi Talati, Kendra L Sweet
Selective inhibitors of nuclear export (SINE) are emerging as a potentially efficacious therapeutic strategy for overcoming resistance to conventional chemotherapy for acute myeloid leukemia. SINE specifically block the protein Exportin 1, also known as chromosomal region maintenance 1, leading to nuclear retention of cargo proteins, including several tumor suppressor proteins. Selinexor, a first generation SINE, is currently in early phase clinical studies in various combinations with promising antileukemic and pro-apoptotic activity...
October 2018: International Journal of Hematologic Oncology
Nizar J Bahlis, Heather Sutherland, Darrell White, Michael Sebag, Suzanne Lentzsch, Rami Kotb, Christopher P Venner, Cristina Gasparetto, Aldo Del Col, Paola Neri, Donna Reece, Michael Kauffman, Sharon Shacham, T J Unger, Jacqueline Jeha, Jean-Richard Saint-Martin, Jatin Shah, Christine Chen
Selinexor is an oral inhibitor of the nuclear export protein exportin 1. Preclinical studies demonstrated synergistic antimyeloma activity between selinexor and proteasome inhibitors (PI) through suppression of NF-κB signaling and nuclear retention of tumor suppressor proteins. We tested selinexor in combination with low-dose bortezomib and dexamethasone (SVd) for the treatment of relapsed or refractory multiple myeloma (MM). The primary objectives of this study were to determine the safety profile, overall response rate (ORR), and a recommended phase 2 dose (RP2D) of SVd...
December 13, 2018: Blood
Han Bit Baek, Alan P Lombard, Stephen J Libertini, Aleida Fernandez-Rubio, Ruth Vinall, Regina Gandour-Edwards, Rachel Nakagawa, Kathleen Vidallo, Kristine Nishida, Salma Siddiqui, Hiromi Wettersten, Yosef Landesman, Robert H Weiss, Paramita M Ghosh, Maria Mudryj
Treatment options for high grade urothelial cancers are limited and have remained largely unchanged for several decades. Selinexor (KPT-330), a first in class small molecule that inhibits the nuclear export protein XPO1, has shown efficacy as a single agent treatment for numerous different malignancies, but its efficacy in limiting bladder malignancies has not been tested. In this study we assessed selinexor-dependent cytotoxicity in several bladder tumor cells and report that selinexor effectively reduced XPO1 expression and limited cell viability in a dose dependent manner...
October 2, 2018: Oncotarget
Enyuan Shang, Yiru Zhang, Chang Shu, Chiaki Tsuge Ishida, Elena Bianchetti, Mike-Andrew Westhoff, Georg Karpel-Massler, Markus D Siegelin
XPO1 has recently emerged as a viable treatment target for solid malignancies, including glioblastoma (GBM), the most common primary malignant brain tumor in adults. However, given that tumors become commonly resistant to single treatments, the identification of combination therapies is critical. Therefore, we tested the hypothesis that inhibition of anti-apoptotic Bcl-2 family members and XPO1 are synthetically lethal. To this purpose, two clinically validated drug compounds, the BH3-mimetic, ABT263, and the XPO1 inhibitor, Selinexor, were used in preclinical GBM model systems...
October 18, 2018: Scientific Reports
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
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
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
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
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
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
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
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
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
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
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