selinexor

BACKGROUND: In this ever-expanding treatment landscape, there is a lack of consolidated health-related quality of life (HRQOL) outcomes and utility reports in relapsed or refractory (R/R) large B cell lymphoma (LBCL) to inform health care policy and decision-maker assessments for both old and new products. These assessments can have a direct effect on what treatment options are available to patients and physicians. OBJECTIVE: A systematic literature review (SLR) was performed to understand the HRQOL evidence for treatments in R/R LBCL and identify associated health utility values...

Over the last 20 years, breakthroughs in accessible therapies for the treatment of multiple myeloma (MM) have been made. Nevertheless, patients with MM resistant to immunomodulatory drugs, proteasome inhibitors, and anti-CD38 monoclonal antibodies have a very poor outcome. Therefore, it is necessary to explore new drugs for the treatment of MM. This review summarizes the mechanism of action of selinexor, relevant primary clinical trials, and recent developments in both patients with relapsed/refractory myeloma and patients with newly diagnosed myeloma...

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BACKGROUND: The majority of pancreatic ductal adenocarcinoma (PDAC) patients experience disease progression while on treatment with gemcitabine and nanoparticle albumin-bound (nab)-paclitaxel (GemPac) necessitating the need for a more effective treatment strategy for this refractory disease. Previously, we have demonstrated that nuclear exporter protein exportin 1 (XPO1) is a valid therapeutic target in PDAC, and the selective inhibitor of nuclear export selinexor (Sel) synergistically enhances the efficacy of GemPac in pancreatic cancer cells, spheroids and patient-derived tumours, and had promising activity in a phase I study...

Protein localization is frequently manipulated to favor tumor initiation and progression. In cancer cells, the nuclear export factor CRM1 is often overexpressed and aberrantly localizes many tumor suppressors via protein-protein interactions. Although targeting protein-protein interactions is usually challenging, covalent inhibitors, including the FDA-approved drug KPT-330 (selinexor), were successfully developed. The development of noncovalent CRM1 inhibitors remains scarce. Here, by shifting the side chain of two methionine residues and virtually screening against a large compound library, we successfully identified a series of noncovalent CRM1 inhibitors with a stable scaffold...

The treatment of relapsed/refractory multiple myeloma (MM) has evolved to include several new options. These include new combinations with second generation proteasome inhibitors (PI); second generation immunomodulators, monoclonal antibodies, CAR T cells, bispecific antibodies, selinexor, venetoclax, and many others. Most patients with MM undergo several cycles of remissions and relapse, and therefore need multiple lines of combination therapies. Selecting treatment options for relapsed/refractory MM requires consideration of resistance status to specific classes, and patient-specific factors such as age and other comorbidities should be considered...

BACKGROUND: The intricate relationship between Forkhead box O1 (FOXO1), a well-established tumor suppressor, and breast cancer (BC) remains partially elucidated. This study aims to investigate the mechanistic role of FOXO1 nuclear localization in the context of BC. METHODS: In vitro experiments employed BC cell lines MCF-7 and MDA-MB-175 treated with LOM612, a small molecule activator of FOXO nuclear-cytoplasmic shuttling, and selinexor, an exportin 1 inhibitor...

INTRODUCTION: The BCL-2 inhibitor venetoclax has been widely used in the treatment of acute myeloid leukemia (AML); however, AML patients treated with venetoclax gradually develop resistance. The exportin-1 (XPO1) inhibitor selinexor can synergistically promote the antileukemia activity of venetoclax, but the mechanism remains unclear. METHODS AND RESULTS: Annexin V/7-aminoactinomycin D assays were used to examine the effects of a combination of venetoclax and selinexor (VEN+SEL) on AML cell lines and primary AML cells...

Multiple myeloma (MM) is an incurable haematological cancer. Selinexor is the first-in-class selective inhibitor of nuclear export (SINE) and was newly approved for the treatment of MM. Until now, very few studies have investigated selinexor resistance in MM. Heterogeneous nuclear ribonucleoprotein U (hnRNPU) is an RNA-binding protein and a component of hnRNP complexes. Here we found that hnRNPU regulates MM sensitivity to selinexor. Cell apoptosis assays were performed to compare selinexor-induced cell death in control knockdown (CTR-KD) and hnRNPU knockdown (hnR-KD) MM cells...

BACKGROUND: Extramedullary disease usually implies a dismal outcome in relapsed/refractory multiple myeloma patients, and requires novel treatment approaches. We designed a trial using Selinexor, a nuclear export protein 1 inhibitor, together with anti-B cell maturation antigen (BCMA) chimeric antigen receptor (CAR)-T cell product CT103A to treat these patients, and describe the first two cases in this report. METHODS: Selinexor was administered with a novel two-step schedule in bridging therapy and in maintenance...

Competent T-cells with sufficient levels of fitness combat cancer formation and progression. In multiple myeloma (MM), T-cell exhaustion is caused by several factors including tumor burden, constant immune activation due to chronic disease, age, nutritional status, and certain MM treatments such as alkylating agents and proteasome inhibitors. Many currently used therapies, including bispecific T-cell engagers, anti-CD38 antibodies, proteasome inhibitors, and CART-cells, directly or indirectly depend on the anti-cancer activity of T-cells...

Recurrent endometrial cancer (EC) remains a therapeutic challenge despite advancements in personalized medicine. SIENDO trial showed the potential clinical benefit of selinexor in patients with TP53 wild-type advanced/recurrent EC. The quest for novel therapeutic avenues and approaches continues as researchers seek a glimmer of hope in an area of uncertainty.

Proper subcellular localization is crucial for the functioning of biomacromolecules, including proteins and RNAs. Nuclear transport is a fundamental cellular process that regulates the localization of many macromolecules within the nuclear or cytoplasmic compartments. In humans, approximately 60 proteins are involved in nuclear transport, including nucleoporins that form membrane-embedded nuclear pore complexes, karyopherins that transport cargoes through these complexes, and Ran system proteins that ensure directed and rapid transport...

INTRODUCTION: Multiple new drugs have been approved over the past 5 years for the treatment of relapsed/refractory multiple myeloma (RRMM), and these are being increasingly widely used. Clinicians need to familiarize themselves with common toxicities associated with these drugs and with novel toxicities requiring specific management and supportive care. AREAS COVERED: We review common toxicities associated with agents approved for RRMM in the past 5 years, including the anti-CD38 monoclonal antibody isatuximab, the antibody - drug conjugate belantamab mafodotin, the bispecific antibody teclistamab, the chimeric antigen receptor (CAR) T cell products idecabtagene vicleucel and ciltacabtagene autoleucel, the selective inhibitor of nuclear export compound selinexor, and the drug - peptide conjugate melflufen, as well as toxicities associated with emerging agents for RRMM including additional bispecific antibodies, the BCL-2 inhibitor venetoclax, and the cereblon E3 ligase modulators iberdomide and mezigdomide...

Diffuse large B cell lymphoma (DLBCL) is the most common lymphoid malignancy and displays vast genetic and transcriptomic heterogeneity. Current treatment guidelines recommend frontline chemoimmunotherapy consisting of an anthracycline backbone, which produces cure rates of ~65%. However, the remaining patients will face relapsed or refractory disease, which, even in the era of CAR-T cells, is difficult to treat. In this issue of Cancer Research, Marullo and colleagues investigate the biological underpinnings of the tumor suppressive activity of the newly approved XPO1 inhibitor selinexor in the treatment of lymphoma...

High grade B-cell lymphoma with MYC and BCL2 rearrangements (HGBCL-DH) represents an uncommon B-cell lymphoma (BCL) with aggressive clinical courses and poor prognosis. Despite revolutionary therapeutic advances in BCL, there has been limited treatment progress in HGBCL-DH, thus necessitating additional therapeutic strategies for HGBCL-DH. This study demonstrated that the BET antagonist INCB057643 synergized with the XPO1 inhibitors (selinexor and eltanexor) to decrease cell viability and increase cell apoptosis in HGBCL-DH cells with or without TP53 mutations...

Introduction: Mantle cell lymphoma (MCL) can be stratified into blastoid and classical subtypes based on morphological features, with the former subtype having a poorer prognosis. Despite recent advances in targeted approaches, including multiple bruton tyrosine kinase inhibitors which yield impressive clinical responses and improve prognoses, MCL remains an incurable disease with frequent relapses. Additional therapeutic interventions are therefore unmet medical needs for the management of patients with MCL...

OBJECTIVES: We aimed to evaluate the activity of selinexor, an oral selective inhibitor of nuclear export, in patients with recurrent or metastatic salivary gland tumors (SGT). METHODS: GEMS-001 is an open-label Phase 2 study for patients with recurrent or metastatic SGT with two parts. In Part 1 of the protocol, patients had tumor samples profiled with targeted next generation sequencing as well as immunohistochemistry for androgen receptor, HER-2 and ALK. For Part 2, patients with no targeted therapies available were eligible to receive selinexor 60 mg given twice weekly every 28 days...

Despite recent relevant therapeutic progresses, chronic lymphocytic leukemia (CLL) remains an incurable disease. Selinexor, an oral inhibitor of the nuclear export protein XPO1, is active as single agent in different hematologic malignancies, including CLL. The purpose of this study was to evaluate the anti-tumor effects of selinexor, used in combination with chemotherapy drugs (i.e. fludarabine and bendamustine) or with the PI3Kδ inhibitor idelalisib in CLL. Our results showed a significant decrease in CLL cell viability after treatment with selinexor-containing drug combinations compared to each single compound, with demonstration of synergistic cytotoxic effects...

Exportin-1 (XPO1), the main soluble nuclear export receptor in eukaryotic cells, is frequently overexpressed in diffuse large B-cell lymphoma (DLBCL). A selective XPO1 inhibitor, selinexor, received approval as single agent for relapsed or refractory (R/R) DLBCL. Elucidating the mechanisms by which XPO1 overexpression supports cancer cells could facilitate further clinical development of XPO1 inhibitors. We uncovered here that XPO1 overexpression increases tolerance to genotoxic stress, leading to a poor response to chemoimmunotherapy...