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1.
Front Pharmacol ; 13: 1030991, 2022.
Article in English | MEDLINE | ID: mdl-36506529

ABSTRACT

Neutrophils are central players in the innate immune system. To protect against invading pathogens, neutrophils can externalize chromatin to create neutrophil extracellular traps (NETs). While NETs are critical to host defense, they also have deleterious effects, and dysregulation of NETs formation has been implicated in autoimmune diseases, atherosclerosis and thrombotic conditions, cancer progression and dissemination, and acute respiratory distress syndrome. Here, we report that selinexor, a first-in-class selective inhibitor of nuclear export approved for the treatment of multiple myeloma and diffuse large B-cell lymphoma, markedly suppressed the release of NETs in vitro. Furthermore, we demonstrate a significant inhibitory effect of selinexor on NETs formation, but not on oxidative burst or enzymatic activities central to NETs release such as neutrophil elastase, myeloperoxidase or peptidyl arginine deiminase type IV. The inhibitory effect of selinexor was demonstrated in neutrophils activated by a variety of NETs-inducers, including PMA, TGF-ß, TNF-α and IL-8. Maximal inhibition of NETs formation was observed using TGF-ß, for which selinexor inhibited NETs release by 61.6%. These findings pave the way to the potential use of selinexor in an effort to reduce disease burden by inhibition of NETs.

3.
Blood ; 131(8): 855-863, 2018 02 22.
Article in English | MEDLINE | ID: mdl-29203585

ABSTRACT

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. The most common nonhematologic adverse events (AEs) were nausea (75%), fatigue (70%), anorexia (64%), vomiting (43%), weight loss (32%), and diarrhea (32%), which were primarily grade 1 or 2. The most common grade 3 or 4 AEs were hematologic, particularly thrombocytopenia (45%). Single-agent selinexor showed modest efficacy with an objective response rate (ORR) of 4% and clinical benefit rate of 21%. In contrast, the addition of dexamethasone increased the ORR with all responses of ≥partial response occurring in the 45 mg/m2 selinexor plus 20 mg dexamethasone twice weekly cohort (ORR = 50%). Furthermore, 46% of all patients showed a reduction in MM markers from baseline. Based on these findings, we conclude that selinexor in combination with dexamethasone is active in heavily pretreated MM and propose a RP2D of 45 mg/m2 (80 mg) plus 20 mg dexamethasone given twice weekly. This trial was registered at clinicaltrials.gov as #NCT01607892.


Subject(s)
Dexamethasone/therapeutic use , Hydrazines/therapeutic use , Multiple Myeloma/drug therapy , Neoplasm Recurrence, Local/drug therapy , Triazoles/therapeutic use , Waldenstrom Macroglobulinemia/drug therapy , Adult , Aged , Aged, 80 and over , Antineoplastic Agents, Hormonal/therapeutic use , Drug Therapy, Combination , Female , Humans , Male , Maximum Tolerated Dose , Middle Aged , Multiple Myeloma/pathology , Neoplasm Recurrence, Local/pathology , Prognosis , Safety , Waldenstrom Macroglobulinemia/pathology
4.
Blood ; 129(24): 3175-3183, 2017 06 15.
Article in English | MEDLINE | ID: mdl-28468797

ABSTRACT

Patients with relapsed or refractory (R/R) non-Hodgkin lymphoma (NHL) have a poor prognosis and limited treatment options. We evaluated selinexor, an orally bioavailable, first-in-class inhibitor of the nuclear export protein XPO1, in this phase 1 trial to assess safety and determine a recommended phase 2 dose (RP2D). Seventy-nine patients with various NHL histologies, including diffuse large B-cell lymphoma, Richter's transformation, mantle cell lymphoma, follicular lymphoma, and chronic lymphocytic leukemia, were enrolled. In the dose-escalation phase, patients received 3 to 80 mg/m2 of selinexor in 3- or 4-week cycles and were assessed for toxicities, pharmacokinetics, and antitumor activity. In the dose-expansion phase, patients were treated with selinexor at 35 or 60 mg/m2 The most common grade 3 to 4 drug-related adverse events were thrombocytopenia (47%), neutropenia (32%), anemia (27%), leukopenia (16%), fatigue (11%), and hyponatremia (10%). Tumor biopsies showed decreases in cell-signaling pathways (Bcl-2, Bcl-6, c-Myc), reduced proliferation (Ki67), nuclear localization of XPO1 cargos (p53, PTEN), and increased apoptosis after treatment. Twenty-two (31%) of the 70 evaluable patients had an objective responses, including 4 complete responses and 18 partial responses, which were observed across a spectrum of NHL subtypes. A dose of 35 mg/m2 (60 mg) was identified as the RP2D. These findings suggest that inhibition of XPO1 with oral selinexor at 35 mg/m2 is a safe therapy with encouraging and durable anticancer activity in patients with R/R NHL. The trial was registered at www.clinicaltrials.gov as #NCT01607892.


Subject(s)
Cell Nucleus/metabolism , Hydrazines/administration & dosage , Hydrazines/pharmacokinetics , Lymphoma, Non-Hodgkin/drug therapy , Lymphoma, Non-Hodgkin/metabolism , Triazoles/administration & dosage , Triazoles/pharmacokinetics , Active Transport, Cell Nucleus/drug effects , Adult , Aged , Aged, 80 and over , Anemia/chemically induced , Anemia/metabolism , Anemia/pathology , Apoptosis/drug effects , Cell Nucleus/pathology , Dose-Response Relationship, Drug , Female , Humans , Hydrazines/adverse effects , Hyponatremia/chemically induced , Hyponatremia/metabolism , Hyponatremia/pathology , Lymphoma, Non-Hodgkin/pathology , Male , Middle Aged , Neoplasm Proteins/metabolism , Neutropenia/chemically induced , Neutropenia/metabolism , Neutropenia/pathology , Thrombocytopenia/chemically induced , Thrombocytopenia/metabolism , Thrombocytopenia/pathology , Triazoles/adverse effects
5.
Blood ; 129(24): 3165-3174, 2017 06 15.
Article in English | MEDLINE | ID: mdl-28336527

ABSTRACT

Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892.


Subject(s)
Blast Crisis/drug therapy , Blast Crisis/mortality , Hydrazines/administration & dosage , Leukemia, Myeloid, Acute/drug therapy , Leukemia, Myeloid, Acute/mortality , Triazoles/administration & dosage , Adult , Blast Crisis/blood , Bone Marrow Cells/metabolism , Disease-Free Survival , Female , Humans , Hydrazines/adverse effects , Leukemia, Myeloid, Acute/blood , Male , Middle Aged , Survival Rate , Triazoles/adverse effects
6.
Clin Cancer Res ; 23(6): 1552-1563, 2017 Mar 15.
Article in English | MEDLINE | ID: mdl-27649553

ABSTRACT

Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer.Experimental Design: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor.Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor-mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexor-treated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all.Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer. Clin Cancer Res; 23(6); 1552-63. ©2016 AACR.


Subject(s)
Cell Proliferation/drug effects , Drug Resistance, Neoplasm/genetics , Karyopherins/genetics , Ovarian Neoplasms/drug therapy , Receptors, Cytoplasmic and Nuclear/genetics , Acrylates/administration & dosage , Active Transport, Cell Nucleus/genetics , Animals , Apoptosis/drug effects , Cell Line, Tumor , Cell Survival/drug effects , Female , Humans , Hydrazines/administration & dosage , Karyopherins/antagonists & inhibitors , Mice , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Platinum/administration & dosage , Platinum/adverse effects , Receptors, Cytoplasmic and Nuclear/antagonists & inhibitors , Triazoles/administration & dosage , Xenograft Model Antitumor Assays , Exportin 1 Protein
7.
J Clin Oncol ; 34(26): 3166-74, 2016 09 10.
Article in English | MEDLINE | ID: mdl-27458288

ABSTRACT

PURPOSE: We evaluated the pharmacokinetics (PKs), pharmacodynamics, safety, and efficacy of selinexor, an oral selective inhibitor of nuclear export compound, in patients with advanced soft tissue or bone sarcoma with progressive disease. PATIENTS AND METHODS: Fifty-four patients were treated with oral selinexor twice per week (on days 1 and 3) at one of three doses (30 mg/m(2), 50 mg/m(2), or flat dose of 60 mg) either continuously or on a schedule of 3 weeks on, 1 week off. PK analysis was performed under fasting and fed states (low v high fat content) and using various formulations of selinexor (tablet, capsule, or suspension). Tumor biopsies before and during treatment were evaluated for pharmacodynamic changes. RESULTS: The most commonly reported drug-related adverse events (grade 1 or 2) were nausea, vomiting, anorexia, and fatigue, which were well managed with supportive care. Commonly reported grade 3 or 4 toxicities were fatigue, thrombocytopenia, anemia, lymphopenia, and leukopenia. Selinexor was significantly better tolerated when administered as a flat dose on an intermittent schedule. PK analysis of selinexor revealed a clinically insignificant increase (approximately 15% to 20%) in drug exposure when taken with food. Immunohistochemical analysis of paired tumor biopsies revealed increased nuclear accumulation of tumor suppressor proteins, decreased cell proliferation, increased apoptosis, and stromal deposition. Of the 52 patients evaluable for response, none experienced an objective response by RECIST (version 1.1); however, 17 (33%) showed durable (≥ 4 months) stable disease, including seven (47%) of 15 evaluable patients with dedifferentiated liposarcoma. CONCLUSION: Selinexor was well tolerated at a 60-mg flat dose on a 3-weeks-on, 1-week-off schedule. There was no clinically meaningful impact of food on PKs. Preliminary evidence of anticancer activity in sarcoma was demonstrated.


Subject(s)
Active Transport, Cell Nucleus/drug effects , Antineoplastic Agents/administration & dosage , Hydrazines/administration & dosage , Sarcoma/drug therapy , Soft Tissue Neoplasms/drug therapy , Triazoles/administration & dosage , Administration, Oral , Adolescent , Adult , Aged , Aged, 80 and over , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Biopsy , Canada , Capsules , Disease Progression , Drug Administration Schedule , Drug Compounding , Fasting/blood , Female , Food-Drug Interactions , Humans , Hydrazines/adverse effects , Hydrazines/pharmacokinetics , Male , Middle Aged , New York City , Pharmaceutical Solutions , Postprandial Period , Sarcoma/metabolism , Sarcoma/pathology , Soft Tissue Neoplasms/metabolism , Soft Tissue Neoplasms/pathology , Tablets , Time Factors , Tomography, X-Ray Computed , Treatment Outcome , Triazoles/adverse effects , Triazoles/pharmacokinetics , Young Adult
8.
J Clin Oncol ; 34(34): 4142-4150, 2016 12.
Article in English | MEDLINE | ID: mdl-26926685

ABSTRACT

Purpose This trial evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of selinexor (KPT-330), a novel, oral small-molecule inhibitor of exportin 1 (XPO1/CRM1), and determined the recommended phase II dose. Patients and Methods In total, 189 patients with advanced solid tumors received selinexor (3 to 85 mg/m2) in 21- or 28-day cycles. Pre- and post-treatment levels of XPO1 mRNA in patient-derived leukocytes were determined by reverse transcriptase quantitative polymerase chain reaction, and tumor biopsies were examined by immunohistochemistry for changes in markers consistent with XPO1 inhibition. Antitumor response was assessed according Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. Results The most common treatment-related adverse events included fatigue (70%), nausea (70%), anorexia (66%), and vomiting (49%), which were generally grade 1 or 2. Most commonly reported grade 3 or 4 toxicities were thrombocytopenia (16%), fatigue (15%), and hyponatremia (13%). Clinically significant major organ or cumulative toxicities were rare. The maximum-tolerated dose was defined at 65 mg/m2 using a twice-a-week (days 1 and 3) dosing schedule. The recommended phase II dose of 35 mg/m2 given twice a week was chosen based on better patient tolerability and no demonstrable improvement in radiologic response or disease stabilization compared with higher doses. Pharmacokinetics were dose proportional, with no evidence of drug accumulation. Dose-dependent elevations in XPO1 mRNA in leukocytes were demonstrated up to a dose level of 28 mg/m2 before plateauing, and paired tumor biopsies showed nuclear accumulation of key tumor-suppressor proteins, reduction of cell proliferation, and induction of apoptosis. Among 157 patients evaluable for response, one complete and six partial responses were observed (n = 7, 4%), with 27 patients (17%) achieving stable disease for ≥ 4 months. Conclusion Selinexor is a novel and safe therapeutic with broad antitumor activity. Further interrogation into this class of therapy is warranted.


Subject(s)
Hydrazines/pharmacology , Neoplasms/drug therapy , Triazoles/pharmacology , Active Transport, Cell Nucleus/drug effects , Adult , Aged , Aged, 80 and over , Biopsy , Drug Administration Schedule , Female , Humans , Hydrazines/administration & dosage , Immunohistochemistry , Male , Middle Aged , Neoplasms/pathology , Research Design , Reverse Transcriptase Polymerase Chain Reaction , Treatment Outcome , Triazoles/administration & dosage
9.
Mol Cancer Ther ; 14(7): 1570-81, 2015 Jul.
Article in English | MEDLINE | ID: mdl-25934708

ABSTRACT

Pancreatic cancer is an aggressive and deadly malignancy responsible for the death of over 37,000 Americans each year. Gemcitabine-based therapy is the standard treatment for pancreatic cancer but has limited efficacy due to chemoresistance. In this study, we evaluated the in vitro and in vivo effects of gemcitabine combined with the selective nuclear export (CRM1) inhibitor KPT-330 on pancreatic cancer growth. Human pancreatic cancer MiaPaCa-2 and metastatic pancreatic cancer L3.6pl cell lines were treated with different concentrations of KPT-330 and gemcitabine alone or in combination, and anchorage-dependent/independent growth was recorded. In addition, L3.6pl cells with luciferase were injected orthotopically into the pancreas of athymic nude mice, which were treated with (i) vehicle (PBS 1 mL/kg i.p., 2/week and povidone/pluronic F68 1 mL/kg p.o., 3/week), (ii) KPT-330 (20 mg/kg p.o., 3/week), (iii) gemcitabine (100 mg/kg i.p., 2/week), or (iv) KPT-330 (10 mg/kg) + gemcitabine (50 mg/kg) for 4 weeks. KPT-330 and gemcitabine alone dose-dependently inhibited anchorage-dependent growth in vitro and tumor volume in vivo compared with vehicle treatment. However, the combination inhibited growth synergistically. In combination, KPT-330 and gemcitabine acted synergistically to enhance pancreatic cancer cell death greater than each single-agent therapy. Mechanistically, KPT-330 and gemcitabine promoted apoptosis, induced p27, depleted survivin, and inhibited accumulation of DNA repair proteins. Together, our data suggest that KPT-330 potentiates the antitumor activity of gemcitabine in human pancreatic cancer through inhibition of tumor growth, depletion of the antiapoptotic proteins, and induction of apoptosis.


Subject(s)
Antineoplastic Combined Chemotherapy Protocols/pharmacology , Pancreatic Neoplasms/drug therapy , Xenograft Model Antitumor Assays , Active Transport, Cell Nucleus/drug effects , Animals , Apoptosis/drug effects , Blotting, Western , Cell Adhesion/drug effects , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Survival/drug effects , Cyclin-Dependent Kinase Inhibitor p27/metabolism , Deoxycytidine/administration & dosage , Deoxycytidine/analogs & derivatives , Deoxycytidine/pharmacology , Dose-Response Relationship, Drug , Drug Synergism , Female , Humans , Hydrazines/administration & dosage , Hydrazines/pharmacology , Mice, Nude , Microscopy, Confocal , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Triazoles/administration & dosage , Triazoles/pharmacology , Tumor Burden/drug effects , Gemcitabine
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