The Experts below are selected from a list of 2718 Experts worldwide ranked by ideXlab platform
Sharon Shacham - One of the best experts on this subject based on the ideXlab platform.
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Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Journal of Clinical Oncology, 2019Co-Authors: Jingsong Zhang, William Senapedis, Erkan Baloglu, Sharon Shacham, David D. Chism, Scott T. Tagawa, Paul Monk, Robert S. Alter, William Reichman, Michael KauffmanAbstract:197Background: Overexpression of Exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (eg. p53), and promotes the translation of eIF4E-bound o...
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A phase 3 randomized, controlled, open-label study of selinexor, bortezomib, and dexamethasone (SVd) versus bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM).
Journal of Clinical Oncology, 2018Co-Authors: Sosana Delimpasi, Sharon Shacham, Michael Kauffman, Ludek Pour, Holger W. Auner, Meletios A. Dimopoulos, Alon Rappaport, Lisa Fortin, Jatin J. Shah, Nizar J. BahlisAbstract:TPS8056Background: Selinexor is an oral, selective inhibitor of nuclear export that specifically blocks Exportin 1, leading to the nuclear accumulation & reactivation of tumor suppressor proteins. ...
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Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration
Oncotarget, 2017Co-Authors: Asfar S. Azmi, William Senapedis, Erkan Baloglu, Sharon Shacham, Yosef Landesman, Michael Kauffman, Irfana Muqbil, Amro Aboukameel, Philip A. PhilipAbstract:// Asfar S. Azmi 1 , Yiwei Li 1 , Irfana Muqbil 1 , Amro Aboukameel 1 , William Senapedis 2 , Erkan Baloglu 2 , Yosef Landesman 2 , Sharon Shacham 2 , Michael G. Kauffman 2 , Philip A. Philip 1 and Ramzi M. Mohammad 1 1 Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA 2 Karyopharm Therapeutics Inc., Newton Centre, MA, USA Correspondence to: Ramzi M. Mohammad, email: mohammar@karmanos.org Keywords: XPO1, miR-145, pancreatic cancer, proliferation, migration Received: March 26, 2017 Accepted: June 18, 2017 Published: July 17, 2017 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States with a majority of these patients dying from aggressively invasive and metastatic disease. There is growing evidence that suggests an important role for microRNAs (miRNAs) in the pathobiology of aggressive PDAC. In this study, we found that the expression of miR-145 was significantly lower in PDAC cells when compared to normal pancreatic duct epithelial cells. Here we show that inhibition of the nuclear exporter protein Exportin 1 (XPO1; also known as chromosome maintenance region 1 [CRM1]) by siRNA knockdown or by the Selective Inhibitor of Nuclear Export (SINE) compound (KPT-330; selinexor) increases miR-145 expression in PDAC cells resulting in the decreased cell proliferation and migration capacities. A similar result was obtained with forced expression of miR-145 in PDAC cells. To this end, SINE compound treatment mediated the down-regulation of known miR-145 targets genes including EGFR, MMP1, MT-MMP, c-Myc, Pak4 and Sox-2. In addition, selinexor induced the expression of two important tumor suppressive miRNAs miR-34c and let-7d leading to the up-regulation of p21 WAF1 . These results are the first to report that targeted inhibition of the nuclear export machinery could restore tumor suppressive miRNAs in PDAC that warrants further clinical investigations.
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A method for quantification of Exportin-1 (XPO1) occupancy by Selective Inhibitor of Nuclear Export (SINE) compounds
Oncotarget, 2015Co-Authors: Marsha Crochiere, Erkan Baloglu, Sharon Shacham, Michael Kauffman, Boris Klebanov, Diego Del Alamo, Margaret S. Lee, Scott Donovan, Yosef LandesmanAbstract:// Marsha L. Crochiere 1 , Erkan Baloglu 1 , Boris Klebanov 1 , Scott Donovan 1 , Diego del Alamo 1 , Margaret Lee 1 , Michael Kauffman 1 , Sharon Shacham 1 , Yosef Landesman 1 1 All authors are current or former employees of Karyopharm Therapeutics Inc., Newton, MA, 02459 U.S.A Correspondence to: Marsha L. Crochiere, e-mail: marsha@karyopharm.com Keywords: selinexor, export, occupancy, cancer, resistance Received: August 06, 2015 Accepted: November 18, 2015 Published: December 07, 2015 ABSTRACT Selective Inhibitor of Nuclear Export (SINE) compounds are a family of small-molecules that inhibit nuclear export through covalent binding to cysteine 528 (Cys528) in the cargo-binding pocket of Exportin 1 (XPO1/CRM1) and promote cancer cell death. Selinexor is the lead SINE compound currently in phase I and II clinical trials for advanced solid and hematological malignancies. In an effort to understand selinexor-XPO1 interaction and to establish whether cancer cell response is a function of drug-target engagement, we developed a quantitative XPO1 occupancy assay. Biotinylated leptomycin B (b-LMB) was utilized as a tool compound to measure SINE-free XPO1. Binding to XPO1 was quantitated from SINE compound treated adherent and suspension cells in vitro , dosed ex vivo human peripheral blood mononuclear cells (PBMCs), and PBMCs from mice dosed orally with drug in vivo . Evaluation of a panel of selinexor sensitive and resistant cell lines revealed that resistance was not attributed to XPO1 occupancy by selinexor. Administration of a single dose of selinexor bound XPO1 for minimally 72 hours both in vitro and in vivo . While XPO1 inhibition directly correlates with selinexor pharmacokinetics, the biological outcome of this inhibition depends on modulation of pathways downstream of XPO1, which ultimately determines cancer cell responsiveness.
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KPT-330, a potent and selective Exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin in prostate cancer models
BMC Cancer, 2015Co-Authors: Giovanni Luca Gravina, Dilara Mccauley, Andrea Mancini, Patrizia Sanita, Flora Vitale, Francesco Marampon, Luca Ventura, Yosef Landesman, Michael Kauffman, Sharon ShachamAbstract:Background and aims Increased expression of Chromosome Region Maintenance (CRM-1)/Exportin-1 (XPO-1) has been correlated with poor prognosis in several aggressive tumors, making it an interesting therapeutic target. Selective Inhibitor of Nuclear Export (SINE) compounds bind to XPO-1 and block its ability to export cargo proteins. Here, we investigated the effects of a new class of SINE compounds in models of prostate cancer. Material and methods We evaluated the expression of XPO-1 in human prostate cancer tissues and cell lines. Next, six SINE (KPT-127, KPT-185, KPT-205, KPT-225, KPT-251 and KPT-330) compounds having different potency with broad-spectrum, tumor-selective cytotoxicity, tolerability and pharmacokinetic profiles were tested in a panel of prostate cancer cells representing distinct differentiation/progression states of disease and genotypes. Two SINE candidates for clinical trials (KPT-251 and KPT-330) were also tested in vivo in three cell models of aggressive prostate cancer engrafted in male nude mice. Results and conclusions XPO-1 is overexpressed in prostate cancer compared to normal or hyperplastic tissues. Increased XPO-1 expression, mainly in the nuclear compartment, was associated with increased Gleason score and bone metastatic potential supporting the use of SINEs in advanced prostate cancer. SINE compounds inhibited proliferation and promoted apoptosis of tumor cells, but did not affect immortalized non-transformed prostate epithelial cells. Nuclei from SINE treated cells showed increased protein localization of XPO-1, survivin and cyclin D1 followed by degradation of these proteins leading to cell cycle arrest and apoptosis. Oral administration of KPT-251 and KPT-330 in PC3, DU145 and 22rv1 tumor-bearing nude mice reduced tumor cell proliferation, angiogenesis and induced apoptosis. Our results provide supportive evidence for the therapeutic use of SINE compounds in advanced/castration resistant prostate cancers and warrants further clinical investigation.
Yosef Landesman - One of the best experts on this subject based on the ideXlab platform.
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Abstract 1013: Role of mitochondria and glutamine metabolism in therapy resistance: Combined targeting of estrogen receptor alpha and Exportin 1 in endocrine resistant breast cancers
Endocrinology, 2019Co-Authors: Eylem Kulkoyluoglu Cotul, Yosef Landesman, Kevin Duong, Brandi Patrice Smith, Hua Chang, Zeynep Madak ErdoganAbstract:Majority of breast cancer specific deaths in women with ERα (+) tumor occur due to metastases that are resistant to endocrine therapy. There is a critical need for novel therapeutic approaches to prevent or delay recurrence of ERα (+) tumors. The objective of this study was to elucidate the role of mitochondrial pathways that are activated in the presence of single therapies and undermine therapy effectiveness in ER (+) breast cancers. In our previous studies, we identified Exportin 1 (XPO1), a nuclear export protein, as an important player in endocrine resistance progression. Selinexor (SXR), an XPO1 antagonist, has been evaluated in multiple later stage clinical trials in patients with relapsed and /or refractory hematological and solid tumor malignancies. Using a combination of transcriptomics, kinase arrays, metabolomics and metabolic flux experiments, we identified glutamine metabolism pathways to be rewired during endocrine resistance. In limited media conditions mimicking nutrient deprived tumor microenvironment, endocrine resistant cells were more dependent on mitochondria for energy production. Their glucose and fatty acid dependency decreased in the presence of SXR and cells were more dependent on glutamine. The effect of glutamine was dependent on conversion of the glutamine to glutamate and mitochondrial complex 1 activity. In order to examine metabolites that might result in the observed phenotype we performed GC/MS whole metabolite profiling and identified aminoacid metabolism pathways to be upregulated when cells were treated with SXR. We demonstrated that combined targeting of XPO1 and ERα rewires metabolic pathways and shuts down both glycolytic and mitochondrial pathways that would eventually lead to autophagy. Remodeling metabolic pathways to regenerate new vulnerabilities in endocrine-resistant breast tumors is novel, and given the need for better strategies for improving therapy response of relapsed ERα (+) tumors, our findings show great promise for uncovering the role ERα-XPO1 crosstalk plays in reducing cancer recurrences. Citation Format: Eylem Kulkoyluoglu Cotul, Brandi Patrice Smith, Hua Chang, Yosef Landesman, Kevin Duong, Zeynep Madak Erdogan. Role of mitochondria and glutamine metabolism in therapy resistance: Combined targeting of estrogen receptor alpha and Exportin 1 in endocrine resistant breast cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 1013.
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Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration
Oncotarget, 2017Co-Authors: Asfar S. Azmi, William Senapedis, Erkan Baloglu, Sharon Shacham, Yosef Landesman, Michael Kauffman, Irfana Muqbil, Amro Aboukameel, Philip A. PhilipAbstract:// Asfar S. Azmi 1 , Yiwei Li 1 , Irfana Muqbil 1 , Amro Aboukameel 1 , William Senapedis 2 , Erkan Baloglu 2 , Yosef Landesman 2 , Sharon Shacham 2 , Michael G. Kauffman 2 , Philip A. Philip 1 and Ramzi M. Mohammad 1 1 Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA 2 Karyopharm Therapeutics Inc., Newton Centre, MA, USA Correspondence to: Ramzi M. Mohammad, email: mohammar@karmanos.org Keywords: XPO1, miR-145, pancreatic cancer, proliferation, migration Received: March 26, 2017 Accepted: June 18, 2017 Published: July 17, 2017 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States with a majority of these patients dying from aggressively invasive and metastatic disease. There is growing evidence that suggests an important role for microRNAs (miRNAs) in the pathobiology of aggressive PDAC. In this study, we found that the expression of miR-145 was significantly lower in PDAC cells when compared to normal pancreatic duct epithelial cells. Here we show that inhibition of the nuclear exporter protein Exportin 1 (XPO1; also known as chromosome maintenance region 1 [CRM1]) by siRNA knockdown or by the Selective Inhibitor of Nuclear Export (SINE) compound (KPT-330; selinexor) increases miR-145 expression in PDAC cells resulting in the decreased cell proliferation and migration capacities. A similar result was obtained with forced expression of miR-145 in PDAC cells. To this end, SINE compound treatment mediated the down-regulation of known miR-145 targets genes including EGFR, MMP1, MT-MMP, c-Myc, Pak4 and Sox-2. In addition, selinexor induced the expression of two important tumor suppressive miRNAs miR-34c and let-7d leading to the up-regulation of p21 WAF1 . These results are the first to report that targeted inhibition of the nuclear export machinery could restore tumor suppressive miRNAs in PDAC that warrants further clinical investigations.
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Abstract 1938: Exportin-1 (XPO1) is a novel therapeutic biomarker for patients with neuroblastoma
Tumor Biology, 2017Co-Authors: Basia Galinski, Yosef Landesman, Marcus Luxemburg, Michelle Ewart, Daniel A. WeiserAbstract:Background: Half of patients with high-risk neuroblastoma succumb to disease, yet these patients with inferior outcome cannot be identified at diagnosis despite contemporary risk stratification that integrates MYCN copy number status, tumor histology, and patient age. We have shown that overexpression of Exportin-1 (XPO1) is associated with poor survival in neuroblastoma, affirming what has been identified across a range of malignancies. Selinexor (KPT-330, Karyopharm Therapeutics), an XPO1 inhibitor in early phase clinical trials, inhibits the nuclear to cytoplasmic translocation of tumor suppressor and growth regulatory proteins implicated in oncogenesis. We hypothesized that protein expression level of XPO1 in neuroblastoma cell lines predict the effective response of treatment with selinexor. Methods: We used a panel of early passage patient derived neuroblastoma cell lines including IMR5, NLF, KELLY, NB-EBC1, and SKNSH that are representative of the spectrum and genetic diversity of human disease. Cell lines were treated with varying concentrations of selinexor. RNA and whole cell protein extract as well as nuclear and cytoplasmic fractionated protein was obtained from untreated and treated conditions. Treated and untreated cells were also pelleted, and, along with patient tumor samples, formalin-fixed and paraffin-embedded for microscopic and immunohistochemical (IHC) evaluation. Results: Compared to noncancerous cell lines, neuroblastoma cell lines have high protein and mRNA expression of XPO1; higher expression correlates with greater sensitivity to selinexor. Selinexor treatment reduced XPO1 protein and increased XPO1 mRNA expression, and it lead to nuclear retention of XPO1 cargo such as p53 and survivin. Comparison of microscopic features and protein staining intensity of patient samples with known XPO1 expression is ongoing. Conclusions: This study provides rationale for XPO1 protein abundance as a potential biomarker of therapeutic response to the drug selinexor. By using patient derived neuroblastoma cell lines, we are able to evaluate the response of selinexor and XPO1 expression in the context of this enigmatic disease. These data suggest that initial drug response to selinexor can be predicted early in the course of disease and more investigation of the high expression of XPO1 seen in patients with poor outcome will provide strategies for combinatorial treatment approaches. Citation Format: Basia Galinski, Marcus Luxemburg, Michelle Ewart, Yosef Landesman, Daniel Weiser. Exportin-1 (XPO1) is a novel therapeutic biomarker for patients with neuroblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 1938. doi:10.1158/1538-7445.AM2017-1938
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The Exportin-1 Inhibitor Selinexor Exerts Superior Antitumor Activity when Combined with T-Cell Checkpoint Inhibitors.
Molecular cancer therapeutics, 2017Co-Authors: Matthew R. Farren, Yosef Landesman, Marsha Crochiere, Rebecca C. Hennessey, Reena Shakya, Omar Elnaggar, Gregory S. Young, Kari Kendra, Sivan Elloul, Boris KlebanovAbstract:Selinexor, a selective inhibitor of nuclear export (SINE) compound targeting Exportin-1, has previously been shown to inhibit melanoma cell growth in vivo We hypothesized that combining selinexor with antibodies that block or disrupt T-cell checkpoint molecule signaling would exert superior antimelanoma activity. In vitro, selinexor increased PDCD1 and CTLA4 gene expression in leukocytes and induced CD274 gene expression in human melanoma cell lines. Mice bearing syngeneic B16F10 melanoma tumors demonstrated a significant reduction in tumor growth rate in response to the combination of selinexor and anti-PD-1 or anti-PD-L1 antibodies (P < 0.05). Similar results were obtained in B16F10-bearing mice treated with selinexor combined with anti-CTLA4 antibody. Immunophenotypic analysis of splenocytes by flow cytometry revealed that selinexor alone or in combination with anti-PD-L1 antibody significantly increased the frequency of both natural killer cells (P ≤ 0.050) and CD4+ T cells with a Th1 phenotype (P ≤ 0.050). Further experiments indicated that the antitumor effect of selinexor in combination with anti-PD-1 therapy persisted under an alternative dosing schedule but was lost when selinexor was administered daily. These data indicate that the efficacy of selinexor against melanoma may be enhanced by disrupting immune checkpoint activity. Mol Cancer Ther; 16(3); 417-27. ©2017 AACRSee related article by Tyler et al., p. 428.
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The Second-Generation Exportin-1 Inhibitor KPT-8602 Demonstrates Potent Activity against Acute Lymphoblastic Leukemia
Clinical cancer research : an official journal of the American Association for Cancer Research, 2016Co-Authors: Thomas Vercruysse, Erkan Baloglu, Yosef Landesman, Els Vanstreels, Maarten Jacquemyn, Jasper E. Neggers, Jolien De Bie, Jonathan L. Schmid-burgk, Veit Hornung, William SenapedisAbstract:Purpose: Human Exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibiting 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 to 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily. Here, we investigate and validate the drug-target interaction of KPT-8602 and explore its activity against acute lymphoblastic leukemia (ALL).Experimental Design: We examined the effect of KPT-8602 on XPO1 function and XPO1-cargo as well as on a panel of leukemia cell lines. Mutant XPO1 leukemia cells were designed to validate KPT-8602's drug-target interaction. In vivo, anti-ALL activity was measured in a mouse ALL model and patient-derived ALL xenograft models.Results: KPT-8602 induced caspase-dependent apoptosis in a panel of leukemic cell lines in vitro Using CRISPR/Cas9 genome editing, we demonstrated the specificity of KPT-8602 for cysteine 528 in the cargo-binding groove of XPO1 and validated the drug target interaction. In vivo, KPT-8602 showed potent anti-leukemia activity in a mouse ALL model as well as in patient-derived T- and B-ALL xenograft models without affecting normal hematopoiesis.Conclusions: KPT-8602 is highly specific for XPO1 inhibition and demonstrates potent anti-leukemic activity supporting clinical application of the second-generation SINE compound for the treatment of ALL. Clin Cancer Res; 23(10); 2528-41. ©2016 AACR.
Michael Kauffman - One of the best experts on this subject based on the ideXlab platform.
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Eltanexor (KPT-8602), a second-generation selective inhibitor of nuclear export (SINE) compound, in patients with metastatic castration-resistant prostate cancer (mCRPC).
Journal of Clinical Oncology, 2019Co-Authors: Jingsong Zhang, William Senapedis, Erkan Baloglu, Sharon Shacham, David D. Chism, Scott T. Tagawa, Paul Monk, Robert S. Alter, William Reichman, Michael KauffmanAbstract:197Background: Overexpression of Exportin 1 (XPO1) in malignant cells increases the nuclear export/inactivation of tumor suppressor proteins (eg. p53), and promotes the translation of eIF4E-bound o...
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A phase 3 randomized, controlled, open-label study of selinexor, bortezomib, and dexamethasone (SVd) versus bortezomib and dexamethasone (Vd) in patients with relapsed or refractory multiple myeloma (RRMM).
Journal of Clinical Oncology, 2018Co-Authors: Sosana Delimpasi, Sharon Shacham, Michael Kauffman, Ludek Pour, Holger W. Auner, Meletios A. Dimopoulos, Alon Rappaport, Lisa Fortin, Jatin J. Shah, Nizar J. BahlisAbstract:TPS8056Background: Selinexor is an oral, selective inhibitor of nuclear export that specifically blocks Exportin 1, leading to the nuclear accumulation & reactivation of tumor suppressor proteins. ...
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Exportin 1 (XPO1) inhibition leads to restoration of tumor suppressor miR-145 and consequent suppression of pancreatic cancer cell proliferation and migration
Oncotarget, 2017Co-Authors: Asfar S. Azmi, William Senapedis, Erkan Baloglu, Sharon Shacham, Yosef Landesman, Michael Kauffman, Irfana Muqbil, Amro Aboukameel, Philip A. PhilipAbstract:// Asfar S. Azmi 1 , Yiwei Li 1 , Irfana Muqbil 1 , Amro Aboukameel 1 , William Senapedis 2 , Erkan Baloglu 2 , Yosef Landesman 2 , Sharon Shacham 2 , Michael G. Kauffman 2 , Philip A. Philip 1 and Ramzi M. Mohammad 1 1 Department of Oncology, Barbara Ann Karmanos Cancer Institute, Wayne State University School of Medicine, Detroit, MI, USA 2 Karyopharm Therapeutics Inc., Newton Centre, MA, USA Correspondence to: Ramzi M. Mohammad, email: mohammar@karmanos.org Keywords: XPO1, miR-145, pancreatic cancer, proliferation, migration Received: March 26, 2017 Accepted: June 18, 2017 Published: July 17, 2017 ABSTRACT Pancreatic ductal adenocarcinoma (PDAC) is the third leading cause of cancer related deaths in the United States with a majority of these patients dying from aggressively invasive and metastatic disease. There is growing evidence that suggests an important role for microRNAs (miRNAs) in the pathobiology of aggressive PDAC. In this study, we found that the expression of miR-145 was significantly lower in PDAC cells when compared to normal pancreatic duct epithelial cells. Here we show that inhibition of the nuclear exporter protein Exportin 1 (XPO1; also known as chromosome maintenance region 1 [CRM1]) by siRNA knockdown or by the Selective Inhibitor of Nuclear Export (SINE) compound (KPT-330; selinexor) increases miR-145 expression in PDAC cells resulting in the decreased cell proliferation and migration capacities. A similar result was obtained with forced expression of miR-145 in PDAC cells. To this end, SINE compound treatment mediated the down-regulation of known miR-145 targets genes including EGFR, MMP1, MT-MMP, c-Myc, Pak4 and Sox-2. In addition, selinexor induced the expression of two important tumor suppressive miRNAs miR-34c and let-7d leading to the up-regulation of p21 WAF1 . These results are the first to report that targeted inhibition of the nuclear export machinery could restore tumor suppressive miRNAs in PDAC that warrants further clinical investigations.
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A method for quantification of Exportin-1 (XPO1) occupancy by Selective Inhibitor of Nuclear Export (SINE) compounds
Oncotarget, 2015Co-Authors: Marsha Crochiere, Erkan Baloglu, Sharon Shacham, Michael Kauffman, Boris Klebanov, Diego Del Alamo, Margaret S. Lee, Scott Donovan, Yosef LandesmanAbstract:// Marsha L. Crochiere 1 , Erkan Baloglu 1 , Boris Klebanov 1 , Scott Donovan 1 , Diego del Alamo 1 , Margaret Lee 1 , Michael Kauffman 1 , Sharon Shacham 1 , Yosef Landesman 1 1 All authors are current or former employees of Karyopharm Therapeutics Inc., Newton, MA, 02459 U.S.A Correspondence to: Marsha L. Crochiere, e-mail: marsha@karyopharm.com Keywords: selinexor, export, occupancy, cancer, resistance Received: August 06, 2015 Accepted: November 18, 2015 Published: December 07, 2015 ABSTRACT Selective Inhibitor of Nuclear Export (SINE) compounds are a family of small-molecules that inhibit nuclear export through covalent binding to cysteine 528 (Cys528) in the cargo-binding pocket of Exportin 1 (XPO1/CRM1) and promote cancer cell death. Selinexor is the lead SINE compound currently in phase I and II clinical trials for advanced solid and hematological malignancies. In an effort to understand selinexor-XPO1 interaction and to establish whether cancer cell response is a function of drug-target engagement, we developed a quantitative XPO1 occupancy assay. Biotinylated leptomycin B (b-LMB) was utilized as a tool compound to measure SINE-free XPO1. Binding to XPO1 was quantitated from SINE compound treated adherent and suspension cells in vitro , dosed ex vivo human peripheral blood mononuclear cells (PBMCs), and PBMCs from mice dosed orally with drug in vivo . Evaluation of a panel of selinexor sensitive and resistant cell lines revealed that resistance was not attributed to XPO1 occupancy by selinexor. Administration of a single dose of selinexor bound XPO1 for minimally 72 hours both in vitro and in vivo . While XPO1 inhibition directly correlates with selinexor pharmacokinetics, the biological outcome of this inhibition depends on modulation of pathways downstream of XPO1, which ultimately determines cancer cell responsiveness.
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KPT-330, a potent and selective Exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin in prostate cancer models
BMC Cancer, 2015Co-Authors: Giovanni Luca Gravina, Dilara Mccauley, Andrea Mancini, Patrizia Sanita, Flora Vitale, Francesco Marampon, Luca Ventura, Yosef Landesman, Michael Kauffman, Sharon ShachamAbstract:Background and aims Increased expression of Chromosome Region Maintenance (CRM-1)/Exportin-1 (XPO-1) has been correlated with poor prognosis in several aggressive tumors, making it an interesting therapeutic target. Selective Inhibitor of Nuclear Export (SINE) compounds bind to XPO-1 and block its ability to export cargo proteins. Here, we investigated the effects of a new class of SINE compounds in models of prostate cancer. Material and methods We evaluated the expression of XPO-1 in human prostate cancer tissues and cell lines. Next, six SINE (KPT-127, KPT-185, KPT-205, KPT-225, KPT-251 and KPT-330) compounds having different potency with broad-spectrum, tumor-selective cytotoxicity, tolerability and pharmacokinetic profiles were tested in a panel of prostate cancer cells representing distinct differentiation/progression states of disease and genotypes. Two SINE candidates for clinical trials (KPT-251 and KPT-330) were also tested in vivo in three cell models of aggressive prostate cancer engrafted in male nude mice. Results and conclusions XPO-1 is overexpressed in prostate cancer compared to normal or hyperplastic tissues. Increased XPO-1 expression, mainly in the nuclear compartment, was associated with increased Gleason score and bone metastatic potential supporting the use of SINEs in advanced prostate cancer. SINE compounds inhibited proliferation and promoted apoptosis of tumor cells, but did not affect immortalized non-transformed prostate epithelial cells. Nuclei from SINE treated cells showed increased protein localization of XPO-1, survivin and cyclin D1 followed by degradation of these proteins leading to cell cycle arrest and apoptosis. Oral administration of KPT-251 and KPT-330 in PC3, DU145 and 22rv1 tumor-bearing nude mice reduced tumor cell proliferation, angiogenesis and induced apoptosis. Our results provide supportive evidence for the therapeutic use of SINE compounds in advanced/castration resistant prostate cancers and warrants further clinical investigation.
Dilara Mccauley - One of the best experts on this subject based on the ideXlab platform.
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KPT-330, a potent and selective Exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin in prostate cancer models
BMC Cancer, 2015Co-Authors: Giovanni Luca Gravina, Dilara Mccauley, Andrea Mancini, Patrizia Sanita, Flora Vitale, Francesco Marampon, Luca Ventura, Yosef Landesman, Michael Kauffman, Sharon ShachamAbstract:Background and aims Increased expression of Chromosome Region Maintenance (CRM-1)/Exportin-1 (XPO-1) has been correlated with poor prognosis in several aggressive tumors, making it an interesting therapeutic target. Selective Inhibitor of Nuclear Export (SINE) compounds bind to XPO-1 and block its ability to export cargo proteins. Here, we investigated the effects of a new class of SINE compounds in models of prostate cancer. Material and methods We evaluated the expression of XPO-1 in human prostate cancer tissues and cell lines. Next, six SINE (KPT-127, KPT-185, KPT-205, KPT-225, KPT-251 and KPT-330) compounds having different potency with broad-spectrum, tumor-selective cytotoxicity, tolerability and pharmacokinetic profiles were tested in a panel of prostate cancer cells representing distinct differentiation/progression states of disease and genotypes. Two SINE candidates for clinical trials (KPT-251 and KPT-330) were also tested in vivo in three cell models of aggressive prostate cancer engrafted in male nude mice. Results and conclusions XPO-1 is overexpressed in prostate cancer compared to normal or hyperplastic tissues. Increased XPO-1 expression, mainly in the nuclear compartment, was associated with increased Gleason score and bone metastatic potential supporting the use of SINEs in advanced prostate cancer. SINE compounds inhibited proliferation and promoted apoptosis of tumor cells, but did not affect immortalized non-transformed prostate epithelial cells. Nuclei from SINE treated cells showed increased protein localization of XPO-1, survivin and cyclin D1 followed by degradation of these proteins leading to cell cycle arrest and apoptosis. Oral administration of KPT-251 and KPT-330 in PC3, DU145 and 22rv1 tumor-bearing nude mice reduced tumor cell proliferation, angiogenesis and induced apoptosis. Our results provide supportive evidence for the therapeutic use of SINE compounds in advanced/castration resistant prostate cancers and warrants further clinical investigation.
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Erratum to: KPT-330, a potent and selective Exportin-1 (XPO-1) inhibitor, shows antitumor effects modulating the expression of cyclin D1 and survivin in prostate cancer models
BMC cancer, 2015Co-Authors: Giovanni Luca Gravina, Dilara Mccauley, Andrea Mancini, Patrizia Sanita, Flora Vitale, Francesco Marampon, Luca Ventura, Yosef Landesman, Michael Kauffman, Sharon ShachamAbstract:Background and aims Increased expression of Chromosome Region Maintenance (CRM-1)/Exportin-1 (XPO-1) has been correlated with poor prognosis in several aggressive tumors, making it an interesting therapeutic target. Selective Inhibitor of Nuclear Export (SINE) compounds bind to XPO-1 and block its ability to export cargo proteins. Here, we investigated the effects of a new class of SINE compounds in models of prostate cancer.
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abstract 501 inhibition of Exportin 1 xpo1 by selinexor kpt 330 synergistically suppresses growth of neuroblastoma in combination with doxorubicin or bromodomain inhibition
Cancer Research, 2015Co-Authors: Pietro J Ranieri, William Senapedis, Dilara Mccauley, Sharon Shacham, Yosef Landesman, Michael Kauffman, Rebecca Trillo, John M Maris, Edward F AttiyehAbstract:Background: Neuroblastoma is a childhood malignancy of the peripheral nervous system, and most patients with high-risk disease are not cured. Exportin 1 (XPO1; Chromosome Region Maintenance 1 Protein Homolog, CRM1) is the sole nuclear exporter of TP53, FOXO1, RB1, CDKN1A, and other critical tumor suppressor proteins (TSPs) and is abundantly expressed in high-risk neuroblastoma. In addition, these major tumor suppressor proteins are rarely mutated in neuroblastoma, and thus inhibition of XPO1 is a rational anti-neuroblastoma strategy. The orally bioavailable drug selinexor (KPT-330) is a selective inhibitor of nuclear export that forms a slowly reversible covalent bond to XPO1 and inhibits XPO1-mediated nuclear export. We previously showed that selinexor showed cytotoxicity with sensitivity independent of MYCN amplification status resulting in decreased Myc family protein levels and activation of apoptotic pathways. In addition, flank xenograft models and mouse models of metastatic disease showed significant tumor growth inhibition across multiple neuroblastoma cell lines. Methods: A time course microarray experiment was performed to discover temporal effects across four neuroblastoma cell lines following exposure to selinexor. Models were selected at the extremes of drug sensitivity and expression profiles were generated after 8 and 24 hours of selinexor exposure. Results: The intersection of linear and K-clustering methods revealed genes that followed a consecutively increasing or decreasing profile with respect to time. There were 4 genes in common to all cell lines, 29 genes across 3 cell lines, and 88 between the two most sensitive cell lines. Based off these observations, MAST3, GPRIN1, SMACRD2, and SENP5 were further explored in a larger cohort of neuroblastoma cell lines. In addition, gene set enrichment analysis revealed a doxorubicin-sensitivity expression profile in more resistant lines after exposure to selinexor. The combination of selinexor and doxorubicin resulted in synergistic increases in cell death. Chromatin remodeling genes were significantly disrupted by selinexor across all models, and the combination of selinexor and the bromodomain inhibitor JQ1 resulted in decreased MYCN protein levels and also showed evidence of synergy in vitro. Conclusions: Expression profiling of neuroblastoma cell lines following selinexor exposure has uncovered candidate biomarkers of activity and sensitivity. The potent synergy with other chemotherapeutic agents provides evidence for rational drug combinations. Selinexor is currently in pediatric phase 1 trials and has the potential to be rapidly translated into a novel therapeutic approach for children with neuroblastoma. Citation Format: Pietro J. Ranieri, Rebecca Trillo, Yosef Landesman, William Senapedis, Dilara McCauley, Sharon Shacham, Michael Kauffman, John M. Maris, Edward F. Attiyeh. Inhibition of Exportin 1 (XPO1) by selinexor (KPT-330) synergistically suppresses growth of neuroblastoma in combination with doxorubicin or bromodomain inhibition. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 501. doi:10.1158/1538-7445.AM2015-501
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preclinical antitumor efficacy of selective Exportin 1 inhibitors in glioblastoma
Neuro-oncology, 2015Co-Authors: Adam L Green, Dilara Mccauley, Shakti Ramkissoon, Kristen Jones, Jennifer A Perry, Jessie Haoru Hsu, Lori A Ramkissoon, Cecile L Maire, Benjamin Hubbellengler, David S KnoffAbstract:Background. Glioblastoma (GBM) is poorly responsive to current chemotherapy. The nuclear transporter Exportin 1 (XPO1, CRM1) is often highly expressed in GBM, which may portend a poor prognosis. Here, we determine the efficacy of novel selective inhibitors of nuclear export (SINE) specific to XPO1 in preclinical models of GBM. Methods. Seven patient-derived GBM lines were treated with 3 SINE compounds (KPT-251, KPT-276, and Selinexor) in neurosphere culture conditions. KPT-276 and Selinexor were also evaluated in a murine orthotopic patient-derived xenograft (PDX) model of GBM. Cell cycle effects were assayed by flow cytometry in vitro and immunohistochemistry in vivo. Apoptosis was determined by terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) and caspase 3/7 activity assays. Results. Treatment of GBM neurosphere cultures with KPT-276, Selinexor, and KPT-251 revealed dose-responsive growth inhibition in all 7 GBM lines [range of half-maximal inhibitory concentration (IC50), 6‐354 nM]. In an orthotopic PDX model, treatment with KPT-276 and Selinexor demonstrated pharmacodynamic efficacy, significantly suppressed tumor growth, and prolonged animal survival. Cellular proliferation was not altered with SINE treatment. Instead, induction of apoptosis was apparent both in vitro and in vivo with SINE treatment, without overt evidence of neurotoxicity. Conclusions. SINE compounds show preclinical efficacy utilizing in vitro and in vivo models of GBM, with induction of apoptosis as the mechanism of action. Selinexor is now in early clinical trials in solid and hematological malignancies. Based on these preclinical data and excellent brain penetration, we have initiated clinical trials of Selinexor in patients with relapsed GBM.
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In Vitro and in Vivo Quantification of Exportin-1 (XPO1) Occupancy By the Oral Selective Inhibitor of Nuclear Export (SINE) Selinexor in Multiple Myeloma, Acute Myeloid Leukemia, and Healthy PBMCs
Blood, 2014Co-Authors: Marsha Crochiere, Sharon Tamir, William Senapedis, Erkan Baloglu, Boris Klebanov, Ori Kalid, Trinayan Kashyap, Diego Del Alamo, Tami Rashal, Dilara MccauleyAbstract:![Graphic][1] Introduction: SINE are a family of small molecules that selectively inhibit nuclear export by forming a slowly reversible covalent bond with Cysteine 528 (Cys528) in the cargo binding pocket of Exportin 1 (XPO1/CRM1). SINE binding to XPO1 leads to forced nuclear retention and activation of major tumor suppressor proteins (TSPs) such as p53, FOXO, pRB and IkB, resulting in selective death of cancer cells. Selinexor is an orally bioavailable SINE compound currently in human phase I and II clinical trials for advanced hematological and solid cancers. Oral selinexor demonstrates maximal pharmacokinetic exposure at 1-2 hours in humans with associated increases in pharmacodynamic markers of XPO1 inhibition in 2-4 hours that last for up to 48 hours. The goal of this study was to develop a binding assay that would enable quantification of XPO1 occupancy in PBMCs from patients following oral administration of selinexor. Methods: To measure the binding of SINE to XPO1, biotinylated leptomycin B (LMB) was utilized. Biotinylated LMB binds covalently and irreversibly to Cys528 in the cargo-binding site of free XPO1 with activity confirmed to be similar to that of unmodified LMB in cytotoxicity assays. To measure SINE binding to XPO1 in vitro, cancer cell lines and PBMCs from normal human donors were treated with SINE compounds prior to treatment with biotinylated LMB. Any XPO1 that did not bind SINE instead binds to biotinylated LMB and can be quantified. In in vivo studies, mice were treated with selinexor, followed by collection of PBMCs for treatment with biotinylated LMB. After incubation with biotinylated LMB, cells were harvested, lysed, and protein lysates were subjected to pull-down experiments with streptavidin-conjugated beads followed by immunoanalysis of XPO1. Results: To evaluate selinexor-XPO1 binding kinetics in vitro, MM.1S, AML2, AML3, and HEL cells were treated with 0 - 10 µM of SINE compounds and unbound XPO1 was pulled down from cell lysates treated with biotinylated LMB. Immunoanalysis showed that 50% XPO1 occupancy with selinexor was achieved at 0.07 µM in MM.1S, 0.1 µM in AML2, 0.03 µM in AML3, and 0.12 µM in HEL cells. Selinexor-XPO1 occupancy experiments using human PBMCs isolated from donor whole blood showed 50% XPO1 occupancy at 0.05 µM. In mice, 50% XPO1 occupancy in PMBCs was achieved after 4 hours treatment with 1.2 mg/kg (3.6 mg/m2) selinexor, while 90% XPO1 occupancy was achieved at 8.1 mg/kg (24.3 mg/m2). Mice treated with a single dose of selinexor from 1.5 to 10 mg/kg for 4-96 hours revealed sustained, dose dependent XPO1 occupancy in PBMCs for up to 72 hours. Conclusions: We have developed a sensitive and robust assay to measure selinexor binding to XPO1 that can be used to evaluate drug exposure following treatment with oral selinexor in preclinical and clinical studies. Studies are ongoing to determine whether there is a correlation between XPO1 occupancy (pharmacodynamics measurement) with disease response in patients with solid and hematological malignancies. Disclosures Crochiere: Karyopharm: Employment. Klebanov: Karyopharm Therpeutics: Employment. Baloglu: Karyopharm: Employment. Kalid: Karyopharm Therapeutics: Employment. Kashyap: Karyopharm Therapeutics: Employment. Senapedis: Karyopharm: Employment. del Alamo: Karyopharm: Employment. Rashal: Karyopharm Therapeutics: Employment. Tamir: Karyopharm: Employment. McCauley: Karyopharm Therapeutics: Employment, Equity Ownership. Carlson: Karyopharm Therapeutics: Employment. Savona: Karyopharm: Consultancy, Equity Ownership; Gilead: Consultancy; Incyte: Consultancy; Celgene: Consultancy. Kauffman: Karyopharm Therapeutics, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Shacham: Karyopharm Therapeutics, Inc: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties. Landesman: Karyopharm Therapeutics: Employment. [1]: /embed/inline-graphic-2.gif
Carolin Bier - One of the best experts on this subject based on the ideXlab platform.
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tfiia transcriptional activity is controlled by a cleave and run Exportin 1 taspase 1 switch
Journal of Molecular Cell Biology, 2018Co-Authors: Christian Schrenk, Verena Fetz, Cecilia Vallet, Christina Heiselmayer, Elisabeth Schröder, Astrid Hensel, Angelina Hahlbrock, Désirée Wünsch, Dorothee Goesswein, Carolin BierAbstract:Transcription factor TFIIA is controlled by complex regulatory networks including proteolysis by the protease Taspase 1, though the full impact of cleavage remains elusive. Here, we demonstrate that in contrast to the general assumption, de novo produced TFIIA is rapidly confined to the cytoplasm via an evolutionary conserved nuclear export signal (NES, amino acids 21VINDVRDIFL30), interacting with the nuclear export receptor Exportin-1/chromosomal region maintenance 1 (Crm1). Chemical export inhibition or genetic inactivation of the NES not only promotes TFIIA's nuclear localization but also affects its transcriptional activity. Notably, Taspase 1 processing promotes TFIIA's nuclear accumulation by NES masking, and modulates its transcriptional activity. Moreover, TFIIA complex formation with the TATA box binding protein (TBP) is cooperatively enhanced by inhibition of proteolysis and nuclear export, leading to an increase of the cell cycle inhibitor p16INK, which is counteracted by prevention of TBP binding. We here identified a novel mechanism how proteolysis and nuclear transport cooperatively fine-tune transcriptional programs.
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TFIIA transcriptional activity is controlled by a ‘cleave-and-run’ Exportin-1/Taspase 1-switch
Journal of molecular cell biology, 2017Co-Authors: Christian Schrenk, Verena Fetz, Cecilia Vallet, Christina Heiselmayer, Elisabeth Schröder, Astrid Hensel, Angelina Hahlbrock, Désirée Wünsch, Dorothee Goesswein, Carolin BierAbstract:Transcription factor TFIIA is controlled by complex regulatory networks including proteolysis by the protease Taspase 1, though the full impact of cleavage remains elusive. Here, we demonstrate that in contrast to the general assumption, de novo produced TFIIA is rapidly confined to the cytoplasm via an evolutionary conserved nuclear export signal (NES, amino acids 21VINDVRDIFL30), interacting with the nuclear export receptor Exportin-1/chromosomal region maintenance 1 (Crm1). Chemical export inhibition or genetic inactivation of the NES not only promotes TFIIA's nuclear localization but also affects its transcriptional activity. Notably, Taspase 1 processing promotes TFIIA's nuclear accumulation by NES masking, and modulates its transcriptional activity. Moreover, TFIIA complex formation with the TATA box binding protein (TBP) is cooperatively enhanced by inhibition of proteolysis and nuclear export, leading to an increase of the cell cycle inhibitor p16INK, which is counteracted by prevention of TBP binding. We here identified a novel mechanism how proteolysis and nuclear transport cooperatively fine-tune transcriptional programs.
