Prognostic and functional role of the nuclear export receptor 1 (XPO1) in gastrointestinal cancers: a potential novel target?

Introduction

Despite growing insights into tumor biology and therapeutic improvements in recent decades, the identification of novel targets for personalized cancer therapy remains of great interest. This has provided a significant boost to the field of cancer genetics, which focuses primarily on identifying genes that cause cancer, facilitate its progression, or alter the response to treatments [ 1 , 2 ]. In recent years, molecular profiling of tumor tissues using novel technologies, such as next-generation sequencing, has revolutionized the therapeutic management of cancer patients, and led to the discovery of new targetable molecular alterations [ 3 ]. The resulting challenge is to integrate these alterations into a personalized treatment approach that targets key molecules driving cancer growth and progression, while also offering more precise therapies based on the unique genomic changes of each individual`s tumor.

Targeting nuclear export proteins has emerged as a viable strategy for cancer therapy [ 4 , 5 ]. These proteins are integral to the transport of macromolecules from the nucleus to the cytoplasm, thereby maintaining cellular homeostasis and regulating essential cellular processes, including gene expression, cell cycle progression, and signal transduction. Dysregulation or aberrant localization of nuclear export proteins often leads to the loss of their functional integrity, contributing to oncogenesis and tumor progression [ 6 – 9 ]. The localization of tumor suppressor proteins (TSPs) is regulated by the nuclear export protein Exportin-1, also known as chromosome region maintenance 1 (CRM1) or XPO1 [ 10 , 11 ]. XPO1 is a member of the importin-β superfamily of karyopherins and the major exporter from the nucleus for the majority of proteins, some mRNAs, rRNAs, and snRNAs [ 10 ]. Aberrant function of XPO1 (via overexpression or mutations) can enhance the nuclear export of tumor suppressors and pro-apoptotic factors, while retaining oncogenic factors in the nucleus. Thus, inhibiting XPO1-mediated nuclear export can restore the normal function of these proteins and induce cell cycle arrest, apoptosis, and senescence in cancer cells [ 12 ]. Several small-molecule inhibitors targeting XPO1 have been developed and tested in preclinical and clinical studies. The most advanced XPO1 inhibitor is selinexor, which has been approved by the FDA for the treatment of relapsed or refractory multiple myeloma (MM) and diffuse large B-cell lymphoma (DLBCL), and is currently being studied in multiple clinical trials for various other malignancies [ 13 – 15 ]. Preclinical data support the potential role of XPO1 as a promising therapeutical target also in gastrointestinal (GI) malignancies. Especially in pancreatic ductal adenocarcinoma (PDAC), the inhibition of XPO1 may suppress cell proliferation and induce apoptosis [ 16 , 17 ]. However, the biological and clinical role of XPO1 in GI cancers is widely unclear and the efficacy of selective inhibitors of nuclear export (also called SINEs or SINE compounds) has yet to be validated.

In this review, we will discuss functional, pathophysiological and clinical implications of XPO1 in GI malignancies.

Main text

Structure of XPO1 gene and protein

The human XPO1 gene is located on chromosome 2p15 [ 18 ]. It consists of 62,710 bases and is oriented on the minus strand [ 19 ]. The XPO1 gene contains 25 exons and 24 introns [ 18 ], and consists of 1071 amino acids [ 19 , 20 ], which are organized in 20 or 21 HEAT motifs (H1–H21), depending on numbering convention [ 21 – 24 ]. A HEAT motif comprises two antiparallel α helices, which are linked by a short loop. The XPO1 protein, which has a molecular weight of 120 kDa, is composed of three main domains: the importin-beta N-terminal domain, the exportin-1-like protein domain and the C-terminal domain (Fig. 1 a, b) [ 25 ]. Since the close proximity of the N-terminal and the C-terminal HEAT, XPO1 has a ring shaped protein form (Fig. 1 b) [ 26 ]. Between H11 and H12 repeats, there is a hydrophobic groove to bind to nuclear export signal (NES) peptides [ 24 , 26 , 27 ]. XPO1 cargo proteins carry a so-called leucine-rich NES motif [ 11 , 26 ]. Especially, Cys528 plays a pivotal role in the structural integrity of XPO1 and its ability to anchor cargo proteins during the export process. Furthermore, it is also the target of specific XPO1 inhibitors [ 28 , 29 ]. Fig. 1 a Domains of XPO1 protein: Importin-beta N-terminal domain, Exportin-1-like protein, XPO1 C terminal domain. b Ring shaped structure of XPO1, domains and Cys528 residue. (orange: Importin-beta N-terminal domain, yellow: Exportin-1-like protein, blue: C terminal domain)

Biological and physiological function of XPO1

In eukaryotic cells, ions and small molecules (< 40 kDa) diffuse across the nuclear membrane following a diffusion gradient [ 30 ]. Larger molecules (> 40 kDa) require active transport for their translocation between the nucleus and cytoplasm [ 31 ]. This process is mediated by the nuclear pore complex (NPC) that facilitates the exchange of hundreds of macromolecules per minute using various transport receptors [ 11 , 30 , 32 – 34 ]. The karyopherin family predominately governs nuclear transport, encompassing two main sub-families: importins and exportins [ 35 , 36 ]. To date, more than ten different importins and seven distinct exportins have been identified [ 37 ], including XPO1, which recognizes leucine-rich hydrophobic NES [ 13 , 36 ].

XPO1, initially identified in the yeast Schizosaccharomyces pombe in 1989, was subsequently established as a critical exporter in Schizosacchiaromyces cerevisiae , responsible for protein and mRNA transport from the nucleus to the cytoplasm [ 30 , 33 , 35 , 38 ]. XPO1 belongs to the importin ß superfamily of nuclear transport receptors and mediates the nuclear export of NES-containing proteins and RNAs (Fig. 2 ) [ 32 , 35 ]. Fig. 2 Transport mechanism of XPO1-mediated nuclear export of protein and RNA cargoes Left: Schematic representation of the transport of RNA cargoes by XPO1. Right: Schematic representation of the transport of protein cargoes by XPO1. In both cases, XPO1 forms a complex with RanGTP and the protein cargoes (or RNA cargoes and adapter protein), which is transported through the NPC. The complex then disassembles in the cytoplasm, converting RanGTP to RanGDP and releasing the XPO1 cargoes into the cytoplasm. XPO1 then migrates back into the nucleus and repeats the whole process. Created with BioRender.com

The transport process is powered by the Ran-GTPase, which maintains a Ran-GTP-Ran-GDP gradient across the nuclear envelope [ 26 , 32 ]. XPO1 binds NES-tagged cargo proteins or RNA adaptor proteins along with Ran-GTP, forming a complex that translocates through the NPC [ 26 , 32 ]. Once in the cytoplasm, Ran-GTP is hydrolyzed to Ran-GDP by GTPase-activating protein (RanGAP), while RCC1 converts Ran-GDP back to Ran-GTP, allowing XPO1 to dissociate from its cargo and return to the nucleus [ 26 , 30 , 32 , 33 , 35 ]. XPO1 also has a vital role in spindle assembly, ensuring microtubule stability at kinetochores and maintaining chromosome integrity [ 39 – 41 ]. It is essential for microtubule formation from kinetochores and interacts with pericentrin at centrosomes during the cell cycle [ 41 ]. The functionality of XPO1 is crucial for cell homeostasis and mitotic regulation [ 40 ], and any dysfunction or aberration in XPO1 activity can significantly impair normal cellular operations.

Structural insights into XPO1 alterations and their functional impact

Several studies have focused on the identification of molecular alterations of XPO1 and their clinical implication. For instance, missense substitutions in XPO1 have been reported in chronic lymphocytic leukemia (CLL) [ 42 , 43 ] and esophageal squamous cell carcinoma (ESCC) [ 44 ], and moreover, a heterozygous mutation hotspot ( XPO1 E571K ) was detected in various malignancies, such as primary mediastinal diffuse large B-cell lymphoma (PMBL) and classical Hodgkin's lymphoma (cHL) [ 45 , 46 ]. So far, the role of this mutation has not been determined and it has not been found to alter the nuclear export function. Of note, no differences in the respond to SINEs were observed in wild-type or XPO1 E571K -mutant cells [ 46 , 47 ].

In a recent study, whole-exome and -genome sequencing was conducted on a large cohort of 42,793 cancer patients, comprising 322 different cancer entities. This comprehensive analysis revealed hotspot mutations in XPO1 , with notable mutations at positions XPO1 E571 , XPO1 R749 and XPO1 D624 [ 48 ]. Among them, the XPO1 E571K mutation ( NM_003400 , chr2:g61718472C > T) was found to be the most common XPO1 mutation in PMBL (33%), cHL (14%), DLBCL (2%) and CLL (3%) [ 48 ]. These observations indicate that this gain-of-function mutations transform XPO1 into an oncogenic driver [ 26 , 32 ]. Although the exact mechanism underlying its oncogenic properties has not been fully understood, the E571K amino acid substitution has been shown to modify the binding preferences of XPO1 for specific nuclear export cargo, possibly mediated by changes in the hydrophobic NES-binding groove [ 49 , 50 ].

Of note, in ESCC a specific missense mutation ( XPO1 D624G ) has been described [ 44 ]. The XPO1 D624G mutation leads to a loss of the salt bridge and thus presumably to a decrease in the affinity of interactions. As a result, XPO1 changes its transition from the bound to the unbound state, increasing its export efficiency [ 44 ].

Currently, more clinical studies are necessary to determine the clinical potential of XPO1 alterations and its use as a novel biomarker for diagnosis and prognosis.

The role of XPO1 in malignancies

In healthy cells, the nuclear export of TSPs is crucial since their prolonged retention in the nucleus can lead to transcriptional repression in the absence of DNA damage or oncogenic stimuli [ 51 ]. TSPs are pivotal in preventing cancer development, progression, and drug resistance when appropriately localized within in the nucleus [ 52 ]. They achieve this through multiple mechanisms, including the suppression of cell division, induction of apoptosis, facilitation of DNA damage repair, and inhibition of metastasis [ 53 ].

Overexpression of XPO1 leads to an increased inactivation of TSPs that correlates with poor prognosis in various human hematologic and solid malignancies [ 32 , 34 , 51 ], including GI cancers, such as PDACs [ 54 ], gastric (GC) [ 55 ], and colorectal cancers (CRC) [ 56 ]. In silico analysis for XPO1 mRNA expression has also been shown to be increased in all GI cancer entities compared to non-tumor tissues as shown in Fig. 3 a [ 57 ]. Fig. 3 a XPO1 mRNA expression in gastrointestinal cancer tissues compared to non-tumor tissues. b Selective inhibitor of nuclear export (SINE) mechanism. SINE compounds selectively inhibit XPO1, disrupting the nuclear export of cargo proteins and RNAs and thus preventing their transport to the cytoplasm. (abbreviations: ESCA: Esophageal carcinoma, STAD: Stomach adenocarcinoma, COAD: Colon adenocarcinoma, LIHC: Liver hepatocellular carcinoma, CHOL: Cholangiocarcinoma, PAAD: Pancreatic adenocarcinoma) Created with BioRender.com

Consequently, cancer cells proliferate rapidly due to the absence of TSPs and growth-regulating proteins in the nucleus, emphasizing the critical role of XPO1 in maintaining cellular homeostasis.

XPO1 overexpression enhances the export of cargo to the cytoplasm leading to the mislocalization and subsequent inactivation of TSPs. This mislocalization promotes oncogenesis by facilitating cell proliferation, cell division, and inhibition of apoptosis induction [ 13 , 52 ]. Consequently, cancer cells proliferate rapidly due to the absence of TSPs in maintaining cellular homeostasis [ 58 ]. Correlation between increased copy number and XPO1 overexpression was reported in some leukemia and lymphoma subtypes [ 59 ], although the mechanisms driving XPO1 overexpression in other malignancies remain largely unexplored.

It has been demonstrated that c-Myc induces the transcriptional activation of XPO1 [ 60 ]. Furthermore, the suppression of XPO1 has been evidenced to attenuate the protein expression levels of both c-Myc and epidermal growth factor receptor (EGFR) in diverse malignancies [ 61 – 63 ]. This regulatory cascade offers insights into the observed XPO1 overexpression in neoplasms lacking a concurrent increase in genomic copy number. Elevated XPO1 expression fosters tumorigenesis and is correlated with adverse clinical outcomes including poor prognosis, disease progression, and resistance to therapeutic interventions, thereby resulting in diminished overall survival (OS) or progression-free survival (PFS) across various cancer phenotypes [ 13 , 32 , 33 ]. However, the precise molecular mechanisms governing the upregulation of XPO1 remain a subject of ongoing investigation, emphasizing the imperative of elucidating the functional role and molecular alterations associated with this gene [ 50 ].

Therapeutics targeting XPO1

The research involving the development of XPO1 inhibitors has started several decades ago, in the beginning of the 90’s when the antifungal antibiotic leptomycin B isolated from a strain of Streptomyces , was identified as a potential XPO1 inhibitor [ 64 ] that covalently and irreversibly binds to C528 and occupies its NES-binding groove [ 65 ]. The first clinical trial with leptomycin B was conducted in patients with advanced refractory cancers, but the trial demonstrated severe toxicities without significant clinical response. Thus, no further studies were conducted [ 66 ]. After this, several researcher started to develop semisynthetic and synthetic inhibitors of XPO1. SINE compounds are molecules that promote the intranuclear accumulation of TSPs [ 51 ]. This restoration of TSP function disrupts cancer cell growth. Both leptomycin B and SINE inhibitors bind to the cysteine residue Cysteine-528 in the cargo binding pocket of the XPO1 protein, thereby inhibiting its activity [ 28 , 64 ]. Unlike leptomycin B, the binding of XPO1 by SINE inhibitors is reversible, which reduces toxicity and enhances treatment tolerability [ 67 ].

SINE compounds are a group of structurally related small molecule inhibitors (Fig. 3 b), including KPT-185, KPT-276, KPT-335 (verdinexor), KPT-330 (selinexor), KPT-8602 (eltanexor), KPT-251 and SL-801 (felezonexor). Hindered by poor pharmacokinetics, only a few SINEs (KPT-335, KPT-330, KPT-8602 and SL-801) have entered clinical trials and the most evaluated component to this date is KPT-330 (also known as selinexor).

Selinexor is an orally administered, first-in-class, highly specific, slowly reversible SINE [ 68 ]. Numerous clinical trials have demonstrated the efficacy of selinexor in the treatment of hematological malignancies, including MM, DLBCL and acute myeloid leukemia [ 69 – 71 ]. Moreover, it has also displayed efficacy in solid tumors, such as prostate, ovarian, and CRC [ 72 – 74 ]. The efficacy of selinexor was demonstrated in patients with relapsed and refractory MM by achieving significant responses and prolonged survival rates [ 75 ]. Subsequently, FDA and EMA approved selinexor for the treatment of refractory and relapsed MM. Moreover, selinexor has also been approved for patients with relapsed and refractory DLBCL by the FDA [ 15 , 76 ].

The therapeutic potential of SINEs and their application are continuously evolving. Identification of prognostic biomarkers, refining dose regimens and understanding potential mechanisms of synergy are crucial for successful integration of these drugs into standard cancer treatment algorithms. Another important aspect to be considered is the safety and adverse effects of SINE inhibitors. For instance, among the most common reported side effects of selinexor included gastrointestinal (i.e. nausea, diarrhea) and hematological (i.e. thrombocytopenia, anemia) toxicities [ 77 – 79 ]. Clinical trials including close monitoring, dose modifications and detailed investigation of side effects of SINE's alone or in combination regimes are crucial to optimize patients care and ensure patient well-being during treatment. At the time of writing, a search for clinical studies that are investigating the efficacy of various SINE inhibitors and were registered in the ClinicalTrials.gov database yielded a total of 142 trials (Table 1 ). The majority of clinical trials listed are predominantly conducted in hematological malignancies, confirming the research emphasis on their therapeutic potential within these oncological malignances. Out of the listed studies, 12 trials are dedicated to investigate the role of SINE inhibitors in GI tumors. This research imbalance indicates an urgent need for expanded studies into GI and other solid tumors to truly determine the efficacy of SINE inhibitors in cancer therapy, both individually and in synergy with other therapeutic agents, and their ability to surmount the challenge of drug resistance. Table 1 Summary of all clinical trials currently ongoing Title Phase of the study NCT number Disease Treatments Selinexor, Carfilzomib, and Dexamethasone in treating patients with relapsed or refractory multiple myeloma (SINE) Phase I NCT02199665 Refractory multiple myeloma Drug: selinexor Drug: carfilzomib Drug: dexamethasone Selective inhibitor of nuclear export (SINE) Selinexor (KPT-330) in patients with myelodysplastic syndromes Phase II NCT02228525 Myelodysplastic syndromes Drug: selinexor (KPT-330) Evaluating SINE KPT-330 in treating patients with melanoma that cannot be removed by surgery Phase I NCT02120222 Recurrent melanoma Drug: Selinexor Other: Correlative studies Phase I/II, study of selective inhibitor of nuclear export (SINE) Selinexor (KPT-330) + Sorafenib in acute myeloid leukemia Phase I-II NCT02530476 Leukemia Acute myeloid leukemia Drug: Selinexor Drug: Sorafenib Safety study of the selective inhibitor of nuclear export (SINE) KPT-330 in patients with advanced hematological cancer Phase I NCT01607892 Hematological Malignancies Drug: KPT-330 SHIP (Selinexor in hormone insensitive prostate cancer) Phase II NCT02146833 Prostate cancer Drug: Selinexor Phase 1 trial to evaluate mFOLFOX6 with Selinexor In patients with metastatic colorectal cancer (SENTINEL) Phase I NCT02384850 Colorectal neoplasm Drug: Selinexor Drug: Oxaliplatin Drug: 5-FU 1 more Study of KPT-330 (Selinexor) in female patients with advanced gynaecologic malignancies (SIGN) Phase II NCT02025985 Ovarian Carcinoma Endometrial carcinoma Cervical Carcinoma Drug: selinexor A Phase II study of Selinexor plus Cytarabine and Idarubicin in patients with relapsed/refractory acute myeloid leukemia (AML) Phase II NCT02249091 Acute myeloid leukemia (relapsed/refractory) Drug: Selinexor Drug: Idarubicin Drug: Cytarabine Gemcitabine, Nab-paclitaxel and KPT-330 in advanced pancreatic cancer Phase I-II NCT02178436 Acinar cell adenocarcinoma of the pancreas Duct cell adenocarcinoma of the pancreas Stage IV Pancreatic cancer Drug: Gemcitabine hydrochloride Drug: Selinexor Other: Pharmacological study 2 more Efficacy and safety study of selinexor in relapsed or refractory peripheral T-cell lymphoma or cutaneous T-cell lymphoma Phase II NCT02314247 Peripheral T-cell Lymphoma (PTCL) Cutaneous T-cell lymphoma (CTCL) Drug: Selinexor KPT-330 to treat poorly differentiated lung and gastroenteropancreatic tumors Phase II NCT02250885 Carcinoma, Neuroendocrine Drug: Selinexor Selinexor (KPT-330) in older patients with relapsed AML (SOPRA) Phase II NCT02088541 Acute Myeloid Leukemia (AML) Drug: Selinexor Drug: Hydroxyurea Drug: Ara-C Safety study of KPT-330 (Selinexor) in patients with advanced or metastatic solid tumor cancer Phase I NCT01607905 Solid tumor Drug: Selinexor Drug: Acetaminophen Phase I Trial of Selinexor (KPT-330) and Ifosfamide, Carboplatin, Etoposide (ICE) in Peripheral T-cell lymphoma Phase I NCT03212937 Peripheral T-cell lymphoma Drug: Selinexor Drug: ICE Chemotherapy Study of the safety, tolerability and efficacy of KPT-8602 in participants with relapsed/efractory cancer indications Phase I-II NCT02649790 Relapsed/refractory multiple myeloma (RRMM) Metastatic colorectal cancer (mCRC) Metastatic castration-resistant prostate cancer (mCRPC) Higher risk myelodysplastic syndrome (HRMDS) Acute myeloid leukemia (AML) Newly diagnosed intermediate/high-risk MDS Drug: KPT-8602 Drug: ASTX727 Drug: Dexamethasone Selinexor in initial or refractory and/or relapsed Richter's transformation (SIRRT) Phase II NCT02138786 Richter's transformation Drug: Selinexor Selinexor treatment of advanced relapsed/refractory squamous cell carcinomas (STARRS) Phase II NCT02213133 Squamous cell carcinoma Drug: Selinexor (KPT-330) A phase I trial to assess the effects of food and formulation on PK of KPT-330 in patients with sarcoma Phase I NCT01896505 Sarcoma Drug: KCP-330 A study of drug therapies for salivary gland cancers based on testing of genes Not Applicable NCT02069730 Salivary Gland Cancer Metastatic Advanced Recurrent Drug: Selinexor Drug: EGFR or HER2 Inhibitor Drug: FGFR Inhibitor Drug: C-KIT inhibitor Drug: Anti-androgen Drug: NOTCH inhibitor Drug: MEK or PI3K Inhibitor Phase I Study of KPT330 in Asian Patients Phase I NCT02078349 Solid tumors Drug: KPT-330 Phase 2 Trial of Selinexor (KPT-330) for metastatic triple negative breast cancer (TNBC) Phase II NCT02402764 Breast Cancer Drug: Selinexor Personalized selinexor-based therapy for relapsed/refractory multiple myeloma Phase II NCT04925193 Multiple myeloma in relapse Drug: Selinexor Drug: Pomalidomide Drug: Daratumumab Drug: Carfilzomib Drug: Dexamethasone Selinexor in combination with irinotecan in adenocarcinoma of stomach and distal esophagus Phase I NCT02283359 Esophageal Cancer Gastric cancer Drug: Selinexor Drug: Irinotecan Decitabine and selinexor in combination to reverse drug resistance with standard chemotherapy in ovarian cancer Phase II NCT05983276 Ovarian cancer Drug: Decitabine Drug: Carboplatin Drug: Paclitaxel Drug: Selinexor A study to evaluate safety and efficacy of selinexor versus treatment of physician's choice in participants with previously treated myelofibrosis Phase II NCT04562870 Myelofibrosis Drug: Selinexor Other: Physician's Choice Treatment Selinexor in treating patients with intermediate- and high-risk acute myeloid leukemia or high-risk myelodysplastic syndrome after transplant Phase I NCT02485535 Acute myeloid leukemia de Novo myelodysplastic Syndrome Myelodysplastic syndrome 2 more Other: Laboratory biomarker analysis Drug: Selinexor Selinexor in treating patients with abiraterone acetate and/or enzalutamide refractory metastatic castration-resistant prostate cancer Phase II NCT02215161 Castration levels of testosterone Hormone-resistant prostate cancer Metastatic prostate carcinoma in the soft tissue 3 more Drug: Selinexor Testing atezolizumab with or without selinexor in patients > = 18 years old with alveolar soft part sarcoma, the axiom study Phase II NCT05333458 Advanced alveolar soft part sarcoma Advanced soft tissue sarcoma Metastatic alveolar soft part sarcoma Unresectable alveolar soft part sarcoma Biological: Atezolizumab Procedure: Biopsy Procedure: Biospecimen Collection Procedure: Computed Tomography Procedure: magnetic resonance imaging Drug: Selinexor Selinexor in treating younger patients with recurrent or refractory solid tumors or high-grade gliomas Phase I NCT02323880 Malignant glioma Recurrent brain neoplasm Recurrent childhood central nervous system neoplasm Recurrent Childhood Glioblastoma Recurrent lymphoma Recurrent malignant solid neoplasm Refractory lymphoma Refractory Malignant Solid Neoplasm Refractory primary central nervous system neoplasm WHO Grade 3 Glioma Other: Pharmacological study Drug: Selinexor Low-dose selinexor and choline salicylate for non-hodgkin or hodgkin lymphoma, histiocytic/dendritic cell neoplasm, or relapsed or refractory multiple myeloma Phase I NCT04640779 Recurrent histiocytic and dendritic cell neoplasm Recurrent Hodgkin lymphoma Recurrent Non-Hodgkin lymphoma recurrent plasma cell myeloma Refractory histiocytic and dendritic cell neoplasm Refractory Hodgkin lymphoma Refractory Non-Hodgkin lymphoma Refractory plasma cell myeloma Drug: Choline Salicylate Drug: Selinexor Selinexor in treating patients with relapsed small cell lung cancer Phase II NCT02351505 recurrent small cell lung carcinoma Drug: Selinexor Other: Laboratory Biomarker Analysis Other: Pharmacological study Selinexor and pembrolizumab for the treatment of cisplatin- ineligible or cisplatin-refractory locally advanced or metastatic urothelial carcinoma Phase I-II NCT04856189 Advanced urothelial carcinoma Locally advanced urothelial carcinoma Metastatic urothelial carcinoma Refractory urothelial carcinoma Biological: Pembrolizumab Drug: Selinexor Decitabine and selinexor in treating patients with relapsed or refractory acute myeloid leukemia Phase I NCT02093403 Acute myeloid leukemia Secondary acute myeloid leukemia Untreated adult acute myeloid leukemia Drug: decitabine Drug: selinexor Other: pharmacological study 1 more Study of selinexor and doxorubicin in advanced soft tissue sarcomas Phase I NCT03042819 Soft tissue sarcoma Drug: Selinexor Drug: Doxorubicin Comparing the combination of Selinexor-Daratumumab-Velcade-Dexamethasone (Dara-SVD) with the usual treatment (Dara-RVD) for high-risk newly diagnosed multiple myeloma Phase II NCT06169215 Multiple myeloma Procedure: Biospecimen collection Procedure: Bone marrow biopsy Drug: Bortezomib Procedure: Computed Tomography Biological: Daratumumab Drug: Daratumumab and Hyaluronidase-fihj Drug: Dexamethasone Drug: Lenalidomide Procedure: Magnetic resonance imaging Procedure: Positron Emission Tomography Drug: Selinexor A Study of the drug selinexor with radiation therapy in patients with newly-diagnosed diffuse intrinsic pontine (DIPG) glioma and high-grade glioma (HGG) Phase I-II NCT05099003 Anaplastic astrocytoma Anaplastic astrocytoma, not otherwise specified diffuse intrinsic pontine glioma Diffuse midline glioma, H3 K27M-Mutant Glioblastoma Glioblastoma, not otherwise specified Malignant glioma Procedure: biopsy Procedure: magnetic resonance imaging Radiation: radiation therapy Drug: Selinexor Selinexor, Cyclophosphamide and Prednisone in Myeloma (MUKtwelve) Phase II NCT06212596 Relapsed or refractory multiple myeloma Drug: Selinexor Drug: Cyclophosphamide Drug: Prednisone Selinexor, pomalidomide, and dexamethasone with or without carfilzomib for the treatment of patients with relapsed refractory multiple myeloma, the SCOPE Trial Phase I-II NCT04764942 Recurrent plasma cell myeloma Recurrent plasma cell myeloma Drug: Carfilzomib Drug: Dexamethasone Drug: Pomalidomide Other: Quality-of-life assessment Other: Questionnaire Administration Drug: Selinexor Selinexor and chemotherapy in treating patients with relapsed or refractory acute myeloid leukemia Phase I NCT02299518 Adult acute myeloid leukemia with 11q23 (MLL) abnormalities Adult acute myeloid leukemia with Del(5q) Adult acute myeloid leukemia with Inv(16)(p13;q22) 5 more Drug: mitoxantrone hydrochloride Drug: etoposide Drug: cytarabine Drug: selinexor Other: laboratory biomarker analysis Other: pharmacological study Selinexor, Daratumumab, Carfilzomib and Dexamethasone for the treatment of high-risk, recurrent or refractory multiple myeloma Phase II NCT04756401 Recurrent plasma cell myeloma Refractory plasma cell myeloma Drug: Carfilzomib Biological: Daratumumab Drug: Dexamethasone Other: Quality-of-life assessment Drug: Selinexor NRSTS2021, A risk adapted study evaluating maintenance Pazopanib, limited margin, dose-escalated radiation therapy and Selinexor in Non-Rhabdomyosarcoma soft tissue sarcoma (NRSTS) Phase I–II NCT06239272 Non-rhabdomyosarcoma Adipocytic Neoplasm Liposarcoma Procedure: Surgical resection Radiation: Proton beam radiation therapy Drug: Pazopanib Drug: Ifosfamide Drug: Doxorubicin Drug: Selinexor Selinexor With Combination With Induction/Consolidation Therapy in Acute Myeloid Leukemia Patients Phase II NCT02835222 Untreated Adult Acute Myeloid Leukemia Drug: Cytarabine Drug: Daunorubicin Hydrochloride Drug: Selinexor Phase IB Study to Evaluate the Safety of Selinexor (KPT-330) in Combination with Multiple Standard Chemotherapy or Immunotherapy Agents in Patients with Advanced Malignancies Phase I NCT02419495 Advanced Malignant Solid Neoplasm Clinical Stage III Cutaneous Melanoma AJCC v8 Clinical Stage IV Cutaneous Melanoma AJCC v8 Fallopian Tube Carcinoma Metastatic Lung Non-Small Cell Carcinoma Metastatic Malignant Solid Neoplasm Metastatic Melanoma Metastatic Renal Cell Carcinoma Ovarian Carcinoma Pathologic Stage III Cutaneous Melanoma AJCC v8 and 19 more Drug: Capecitabine Drug: Carboplatin Drug: Cyclophosphamide Drug: Doxorubicin Drug: Eribulin Drug: Fluorouracil Biological: Ipilimumab Drug: Irinotecan Hydrochloride Drug: Leucovorin Calcium Biological: Nivolumab and 7 more KPT-330 Plus RICE for relapsed/refractory aggressive B-cell lymphoma (KPT-330 + RICE) Phase I NCT02471911 Diffuse large B-cell lymphoma Drug: KPT-330 Drug: Rituximab Drug: Etoposide 3 more Selinexor in advanced liposarcoma (SEAL) Phase II–III NCT02606461 Dedifferentiated liposarcoma Drug: Selinexor Drug: Placebo Study evaluating the efficacy and safety of Selinexor (KPT-330) in Participants with recurrent gliomas (KING) Phase II NCT01986348 Glioblastoma Glioma Drug: Selinexor Selinexor treatment of refractory myeloma (STORM) Phase II NCT02336815 Multiple myeloma Drug: Selinexor Drug: Dexamethasone A study to test the combination of Selinexor (KPT-330), Ixazomib, and Dexamethasone in patients with myeloma Phase I NCT02831686 Multiple myeloma Relapsed and/or refractory multiple myeloma Drug: Selinexor Drug: Ixazomib Drug: Dexamethasone Evaluation of activity and safety of oral selinexor in participants with severe COVID-19 infection (Coronavirus) Phase II NCT04349098 Coronavirus infection Drug: Selinexor Other: Placebo Phase 1/2 Trial of Selinexor (KPT-330) With Docetaxel for Non-small Cell Lung Cancer (NSCLC) Phase I–II NCT03095612 Non-small cell lung cancer Drug: Selinexor Drug: Docetaxel A study of evaluating the safety and efficacy of ATG-010 in relapsed refractory multiple myeloma (MARCH) Phase II NCT03944057 Relapse/refractory multiple myeloma Drug: ATG-010 Selinexor (KPT-330) Plus FLAG-Ida for the treatment of relapsing/refractory AML (FLAGINEXOR) Phase I NCT03661515 Acute myeloid leukemia Drug: Selinexor Drug: fludarabine Drug: idarubicin 2 more Selinexor with Fludarabine and Cytarabine for treatment of refractory or relapsed leukemia or myelodysplastic syndrome Phase I NCT02212561 Acute myeloid leukemia (AML) Acute lymphoblastic leukemia (ALL) Myelodysplastic syndrome (MDS) Mixed phenotype acute leukemia (MPAL) Drug: Selinexor Drug: Fludarabine Drug: Cytarabine Drug: methotrexate/hydrocortisone/cytarabine Selinexor in patients with advanced thymic epithelial tumor progressing after primary chemotherapy (SELECT) Phase II NCT03193437 Thymoma Advanced Thymic Epithelial Tumor Drug: Open label Selinexor A trial of Selinexor, Ruxolitinib and Methylprednisolone (KPT-IST-391) Phase I NCT06225310 Multiple myeloma in relapse Multiple myeloma, refractory Drug: Selinexor Drug: Ruxolitinib Drug: Methylprednisolone A Study of Selinexor in combination with Daunorubicin and Cytarabine for Untreated AML Phase I NCT02403310 Leukemia Acute myeloid leukemia AML Drug: Selinexor Drug: Daunorubicin Drug: Cytarabine Selective inhibitor of nuclear export, Selinexor (KPT-330) in combination with paclitaxel and Carboplatin in patients with advanced ovarian or endometrial cancers Phase I NCT02269293 Ovarian Cancer Endometrial cancer Drug: Paclitaxel Drug: Carboplatin Drug: Selinexor A study of selinexor in combination with standard of care therapy for newly diagnosed or recurrent Glioblastoma Phase I-II NCT04421378 Glioblastoma multiforme Drug: Selinexor Drug: Temozolomide (TMZ) Drug: Lomustine (CCNU) Radiation: standard fractionated radiation therapy (RT) Drug: Bevacizumab Device: TTField Drug: Carmustine Selinexor (KPT-330) and Liposomal Doxorubicin For Relapsed and Refractory Multiple Myeloma Phase I–II NCT02186834 Multiple myeloma Drug: Selinexor Drug: Liposomal doxorubicin Drug: Dexamethasone Selinexor with combination chemotherapy in treating patients with acute myeloid leukemia Phase I NCT02573363 Acute myeloid leukemia Drug: Cytarabine Drug: Mitoxantrone Hydrochloride Drug: Selinexor a study to evaluate the safety and efficacy of selinexor with or without pembrolizumab versus standard of care in previously treated metastatic colorectal cancer with RAS mutations Phase II NCT04854434 Metastatic colorectal cancer Drug: Selinexor Drug: Pembrolizumab Drug: Trifluridine Drug: Tipiracil SELINEXOR in Combination w/Bevacizumab and Atezolizumab in newly diagnosed advanced hepatocellular carcinoma Phase I NCT05093608 Hepatocellular carcinoma Drug: Selinexor Pill Drug: Bevacizumab Drug: Atezolizumab A Phase Ib study of oral Selinexor in adult patients with relapsed/refractory B-cell lymphoma receiving R-DHAOx or R-GDP (SELINDA) Phase I NCT02741388 B-cell lymphoma Drug: selinexor Drug: Rituximab Drug: Dexamethasone Drug: Oxaliplatin Drug: Cisplatin Drug: Cytarabine Drug: Gemcitabine Study of CLAG + Selinexor in Relapsed or Refractory Acute Myeloid Leukemia Phase I–II NCT02416908 Acute myeloid leukemia Drug: Selinexor Drug: Cladribine Drug: G-CSF Drug: Cytarabine Procedure: Bone marrow biopsy Adaptive treatment for acute myeloid leukemia based on D14 MRD results (AVS) Phase II NCT05736978 AML MRD Drug: Azacitidine Drug: Venetoclax Drug: Selinexor Treatment of Selinexor in combination with clarithromycin, pomalidomide and dexamethasone for relapsed refractory multiple myeloma patients (ClaSPd) Phase II NCT04843579 Myeloma multiple Myeloma Refractory multiple myeloma Drug: Selinexor Drug: Clarithromycin Drug: Pomalidomide Drug: Dexamethasone Selinexor in combination with fludarabine and cytarabine in patients with refractory or relapsed acute myeloid leukemia Phase II NCT03071276 Acute myeloid leukemia (AML) Drug: Selinexor Drug: Fluarabine Drug: Cytarabine Drug: methotrexate/hydrocortisone/cytarabine Selinexor Plus high-dose Melphalan (HDM) before autologous hematopoietic cell transplantation for multiple myeloma Phase I–II NCT02780609 Multiple myeloma Drug: Selinexor Drug: Melphalan Drug: Dexamethasone Procedure: autologous hematopoietic cell transplantation (HCT) Drug: Fosaprepitant COVID-19 prevention and treatment in cancer; a sequential multiple assignment randomised trial; (C-SMART) Phase III NCT04534725 Cancer Covid19 Respiratory Viral Infection Drug: Interferon alfa Drug: Selinexor Drug: Lenzilumab Multicenter, platform-type clinical study of refractory/recurrent acute myeloid leukemia Not applicable NCT06265545 AML Refractory Relapsed Drug: Ivosidenib Drug: Venetoclax Drug: Gilteritinib Drug: Selinexor Study assessing activity of intravenous (IV) ABBV-383 monotherapy versus standard available therapies in adult participants with relapsed or refractory multiple myeloma Phase III NCT06158841 Multiple myeloma Drug: ABBV-383 Drug: Carfilzomib Drug: Pomalidomide Drug: Elotuzumab Drug: Selinexor Drug: Bortezomib Drug: Dexamethasone Allogeneic stem cell transplantation vs. conventional therapy as salvage therapy for relapsed/progressive patients with multiple myeloma after first-line therapy (AlloRelapseMM) Phase III NCT05675319 Multiple myeloma Drug: Allogeneic Stem Cells Drug: carfilzomib/lenalidomide/dexamethasone (KRD) Drug: elotuzumab/lenalidomide/dexamethasone (ERD) Drug: daratumumab/bortezomib/dexamethasone (DVD) Drug: daratumumab/lenalidomide/dexamethasone (DRD) Drug: ixazomib/lenalidomide/dexamethasone (IRD) Drug: pomalidomide/bortezomib/dexamethasone (PVD) Drug: carfilzomib/daratumumab/dexamethasone (KDD) Drug: Autologous Stem Cells Drug: daratumumab/pomalidomide/dexamethasone (DPD) Drug: isatuximab/carfilzomib/dexamethasone (Isa-KD) Drug: selinexor/bortezomib/dexamethasone (SVD) A study of different dosing schedules of selinexor in sarcoma patients Phase I–II NCT04811196 Soft tissue sarcoma Malignant peripheral nerve sheath tumor (MPNST) Leiomyosarcoma Endometrial Stromal Sarcoma Drug: Selinexor Selinexor plus gemcitabine in selected advanced soft-tissue sarcoma (SeliSarc) Phase I–II NCT06114004 Sarcoma, soft tissue Drug: Selinexor 20 MG Drug: Gemcitabine A real-world study of selinexor-based regimens for treatment of non-Hodgkin lymphoma Observational NCT05852028 Lymphoma DLBCL T Cell Lymphoma Drug: Selinexor A study of Selinexor monotherapy in subjects with JAK Inhibitor (JAKi)-naïve myelofibrosis and moderate thrombocytopenia Phase II NCT05980806 Myelofibrosis Moderate Thrombocytopenia Drug: Selinexor Study of Selinexor combined with chidamide in relapsed/refractory acute leukemia (AML) Patients Phase II NCT05951855 Acute Myeloid Leukemia (Relapsed/Refractory) Drug: Selinexor Drug: Chidamide Selinexor as single agent and with imatinib in metastatic and/or unresectable gastrointestinal stromal tumors (SeliGIST) Phase I–II NCT04138381 Maximum Tolerated Dose GIST Metastatic adult soft tissue sarcoma Drug toxicity Drug Use Drug: Selinexor Drug: Imatinib Selinexor Plus Gemcitabine in selected advanced soft-tissue sarcoma and osteosarcoma Phase I NCT04595994 Sarcoma, soft tissue Drug: Selinexor Selinexor in maintenance therapy after systemic therapy for participants with p53 wild-type, advanced or recurrent endometrial carcinoma Phase III NCT05611931 Endometrial cancer Drug: Selinexor Drug: Matching Placebo for selinexor Selinexor for the treatment of intermediate and high-risk smoldering multiple myeloma Phase II NCT05597345 Smoldering multiple myeloma Drug: Selinexor Selinexor plus combination chemotherapy in treating patients with advanced B cell non-Hodgkin lymphoma Phase I–II NCT03147885 Diffuse large B-cell lymphoma Recurrent B-cell non-Hodgkin lymphoma Recurrent extranodal marginal zone lymphoma Recurrent follicular lymphoma Recurrent indolent adult non-hodgkin lymphoma Recurrent mantle cell lymphoma Recurrent marginal zone lymphoma Recurrent Waldenstrom macroglobulinemia Refractory B-cell non-hodgkin lymphoma Refractory extranodal marginal zone lymphoma and 5 more Drug: Selinexor Selinexor in myelofibrosis refractory or intolerant to JAK1/2 Inhibitors (ESSENTIAL) Phase II NCT03627403 Primary Myelofibrosis Post-essential Thrombocythemia Myelofibrosis Post-polycythemia vera myelofibrosis Drug: Selinexor Selinexor (Nexpovio®) (SVd) in Patients With Relapsed or Refractory Multiple Myeloma (SEATTLE) Observational NCT05954780 Multiple myeloma Drug: Selinexor Selinexor treatment for multiple myeloma patients who are refractory to lenalidomide-containing therapy Phase I NCT04519476 Refractory multiple myeloma Drug: Selinexor Drug: Lenalidomide Drug: Methylprednisolone A study of selinexor in people with wilms tumors and other solid tumors Phase II NCT05985161 Wilms Tumor Rhabdoid Tumor Malignant Peripheral Nerve Sheath Tumors MPNST Nephroblastoma XPO1 Gene Mutation Solid Tumor Drug: Selinexor Selinexor with alternating bortezomib or lenalidomide plus dexamethasone in TIE newly diagnosed MM patients (SABLe) Phase II NCT04717700 Multiple myeloma Drug: Selinexor 20 MG Oral Tablet Drug: Bortezomib injection Drug: Lenalidomide capsule Drug: Dexamethasone oral Selinexor in combination with R-CHOP followed by selinexor maintenance for untreated EBV-positive DLBCL patients Phase I–II NCT05577364 EBV-positive diffuse large B-cell lymphoma, Nos Drug: Selinexor Drug: R-CHOP protocol Selinexor and Lenalidomide for consolidation and maintenance treatment in multiple myeloma post-transplant Phase II NCT05820763 Multiple mMyeloma Myeloma-associated amyloidosis Drug: Selinexor Drug: Lenalidomide Drug: Dexamethasone Study of Selinexor in combination with ruxolitinib in myelofibrosis Phase III NCT04562389 Myelofibrosis Drug: Selinexor Other: Placebo Drug: Ruxolitinib an open, single center, non-randomized, single arm clinical study of evaluating the efficacy of selinexor in the maintenance treatment of PTCL Phase II–III NCT05822050 PTCL patients who achieved complete response from frontline treatment Drug: Selinexor Selinexor combined with R-GemOx as second-line treatment in patients with diffuse large B-cell lymphoma Phase IV NCT05786989 Diffuse Large B-cell lymphoma, not otherwise specified Drug: selinexor A Phase I dose escalation study of selinexor plus nivolumab and ipilimumab in advanced/metastatic solid malignancies Phase I NCT04850755 Advance solid malignancies Metastatic solid malignancies Drug: Selinexor in combination with nivolumab and ipilimumab Phase I trial of the selective inhibitor of nuclear export, KPT-330, in relapsed childhood ALL and AML Phase I NCT02091245 Relapsed acute lymphoblastic leukemia (ALL) Refractory acute lymphoblastic leukemia (ALL) Relapsed acute myelogenous leukemia (AML) Refractory acute myelogenous leukemia (AML) Relapsed mixed lineage leukemia Refractory mixed lineage leukemia Relapsed biphenotypic leukemia Refractory biphenotypic leukemia Chronic myelogenous leukemia (CML) in blast crisis Drug: KPT-330 A study of Selinexor, in combination with Carfilzomib, Daratumumab or Pomalidomide in patients with multiple myeloma Phase II NCT04661137 Multiple myeloma Drug: Selinexor 60 MG Drug: Selinexor 80 MG Drug: Selinexor 100 MG Drug: Carfilzomib Drug: Pomalidomide Drug: Daratumumab Drug: Dexamethasone XPO-1 in combination with RCHOP for DH/TH Lymphoma Phase II NCT05974085 Double Hit Lymphoma Triple hit lymphoma Drug: Selinexor + RCHOP Selinexor Plus VRd in high risk newly diagnosed multiple myeloma Phase I–II NCT05422027 Multiple myeloma Drug: Selinexor Drug: Bortezomib Drug: Lenalidomide Drug: Dexamethasone Selinexor, Pomalidomide, and Dexamethasone For multiple myeloma with CNS involvement (SPODUMENE) Phase II NCT05478993 Multiple myeloma Drug: SPD#Selinexor oral tablet, Pomalidomide, Dexamethasone Selinexor (KPT-330) in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL) Phase II NCT02227251 Diffuse large B-cell lymphoma Drug: Selinexor Selinexor (KPT-330) in combination with Temozolomide and radiation therapy in patients with newly diagnosed glioblastoma Phase I NCT04216329 Gliosarcoma Newly Diagnosed Glioblastoma Drug: Selinexor Drug: Temozolomide Radiation: generic radiation therapy (RT) Maintenance with Selinexor/Placebo After combination chemotherapy in participants with endometrial xancer [SIENDO] (ENGOT-EN5) Phase III NCT03555422 Endometrial cancer Drug: Selinexor Drug: Matching placebo for selinexor Study of Selinexor combined With Olaparib in relapsed/refractory extensive stage small cell lung cancer Phase I–II NCT05975944 Extensive-stage small cell lung cancer Drug: Selinexor#Olaparib Safety and efficacy of Selinexor in combination with Pembrolizumab in recurrent advanced melanoma Phase II NCT04768881 Locally advanced unresectable or metastatic melanoma Drug: Selinexor Drug: Pembrolizumab Study of Selinexor Plus DRd for newly diagnosed multiple myeloma Phase II NCT04782687 Multiple myeloma Myeloma multiple Kahler Disease Myeloma, plasma cell Myeloma-Multiple Myelomatosis Plasma cell myeloma Drug: Selinexor Drug: Dexamethasone Oral Drug: Daratumumab Drug: Lenalidomide ATG-010(Selinexor) in combination with chemotherapy in RRMM Phase II NCT04877275 Multiple myeloma Drug: Selinexor (80 mg/d) Drug: Selinexor (100 mg/d) Drug: Pegylated liposomal doxorubicin Drug: Dexamethasone Drug: Cyclophosphamide Selinexor Plus R-CHOP in High-risk GCB-subtype diffuse large B-cell lymphoma Phase II NCT05422066 DLBCL Germinal Center B-Cell Type Drug: Selinexor Drug: Rituximab Drug: Cyclophosphamide Drug: Doxorubicin Drug: Vincristine Drug: Prednisone Selinexor in combination with immunomodulator (Thalidomide/Pomalidomide/Lenalidomide) in RRMM Phase II NCT04941937 Multiple myeloma Drug: Selinexor Drug: Thalidomide Drug: Lenalidomide Drug: Pomalidomide Drug: Dexamethasone Mechanism investigation of Selinexor combined with Lenalidomide and Rituximab in the treatment of diffuse large B-cell lymphoma Observational NCT05923879 Lymphoma, large B-cell, diffuse Drug: Selinexor combined with lenalidomide and rituximab Selinexor & Talazoparib in advanced Refractory Solid Tumors; advanced/metastatic triple negative breast cancer (START) Phase I–II NCT05035745 Advanced refractory solid tumors Advanced triple negative breast cancers Metastatic triple negative breast cancers Drug: Talazoparib Drug: Selinexor Selinexor in combination With HAD or CAG regimens in relapsed or refractory acute myeloid leukemia Phase III NCT05726110 Relapsed or refractory acute myeloid leukemia Drug: Selinexor Drug: Homoharringtonine Drug: Daunorubicin Drug: Cytarabine Drug: Granulocyte Colony-Stimulating Factor Drug: Aclacinomycin Selinexor, Venetoclax, and Dexamethasone (XVenD) in t(11;14)-positive relapsed/refractory multiple myeloma (SELVEDge) Phase II NCT05530421 Relapsed and refractory multiple myeloma Drug: Selinexor Drug: Venetoclax Drug: Dexamethasone A study of combination of Selinexor, Pomalidomide, and Dexamethasone (SPd) versus Elotuzumab, Pomalidomide, and Dexamethasone (EloPd) in subject With previously treated multiple myeloma Phase III NCT05028348 Multiple myeloma Drug: Selinexor Drug: Elotuzumab Drug: Pomalidomide Drug: Dexamethasone Oral Selinexor and HAAG with/without HMA in relapsed/refractory acute leukemia (AML) Patients Not applicable NCT05805072 Relapsed/refractory AML Drug: Selinexor Drug: Homoharringtonine Drug: Cytarabine Drug: Aclacinomycin Drug: Granulocyte colony-stimulating factor Drug: Decitabine Drug: Azacitidine A study of Selinexor (Seli) + Low-dose Dexamethasone (LDD) in penta-refractory multiple myeloma (MM), Seli and Bortezomib + LDD in Triple-class Refractory MM, and Seli and Pomalidomide + LDD in relapsed refractory MM Phase II NCT04414475 Multiple Myeloma, Refractory Drug: Selinexor Drug: Dexamethasone Drug: Bortezomib Drug: Pomalidomide Study of Selinexor and Venetoclax in combination with chemotherapy in pediatric and young adult patients with refractory or relapsed acute myeloid leukemia Phase I NCT04898894 Acute leukemia of ambiguous lineage in relapse Acute myeloid leukemia, in relapse Refractory acute leukemia of ambiguous lineage Refractory acute myeloid leukemia Drug: Venetoclax Drug: Selinexor Drug: Cytarabine Drug: Fludarabine Biological: Filgrastim Drug: Methotrexate Drug: methotrexate/hydrocortisone/cytarabine Bortezomib, Selinexor, and Dexamethasone in patients with multiple myeloma (BOSTON) Phase III NCT03110562 Multiple myeloma Drug: Selinexor Drug: Bortezomib Drug: Dexamethasone Selinexor in combination with Thalidomide and Dexamethasone in RRMM Phase I–II NCT04891744 Multiple myeloma Drug: Selinexor Drug: Thalidomide Drug: Dexamethasone Selinexor in combination with MTX + Ritu to treat R/R CNSL Phase I–II NCT05698147 Central nervous system lymphoma Drug: Selinexor Drug: Rituximab Drug: Methotrexate Relative bioavailability/bioequivalence of different formulations of Selinexor, the impact of hepatic impairment on Selinexor pharmacokinetics, tolerability and antitumor activity of Selinexor combination treatment (SPRINT) Phase I–II NCT04256707 Non-small cell lung carcinoma (NSCLC) Colorectal cancer (CRC) Other Solid Tumors Drug: Selinexor 100 mg Drug: Docetaxel Drug: Pembrolizumab Drug: FOLFIRI Drug: Selinexor 40 mg Drug: Selinexor 80 mg Drug: Selinexor 60 mg Selinexor combined with R-GDP regimen for TP53-altered R/R DLBCL Phase II NCT06062641 Relapsed or refractory B-cell Lymphoma Drug: SR-GDP Venetoclax and Selinexor in treating patients with relapsed or refractory high risk hematologic malignancies Phase I NCT03955783 Diffuse Large B-cell Lymphoma Acute myeloid leukemia Non-Hodgkin's Lymphoma Drug: Venetoclax Drug: Selinexor Selinexor and backbone treatments of multiple myeloma patients (STOMP) Phase I–II NCT02343042 Multiple myeloma Drug: Selinexor Drug: Dexamethasone Drug: Lenalidomide Drug: Pomalidomide Drug: Bortezomib Drug: Daratumumab Drug: Carfilzomib Drug: Ixazomib Drug: Elotuzumab Drug: Clarithromycin Drug: Belantamab Mafodotin A study of Rituximab-Gemcitabine-Dexamethasone-Platinum (R-GDP) with or without selinexor in patients with relapsed/refractory diffuse large B-cell lymphoma Phase II–III NCT04442022 Relapsed/refractory diffuse large B-cell lymphoma Drug: Selinexor (combination therapy) Drug: Placebo matching for Selinexor (combination therapy) Drug: Rituximab (combination therapy) Drug: Gemcitabine (combination therapy) Drug: Dexamethasone (combination therapy) Drug: Cisplatin (combination therapy) Drug: Selinexor (continuous therapy) Drug: Placebo matching for Selinexor (continuous therapy) A study of Selinexor in combination with Azacitidine and Venetoclax (sav regimen) in treatment naïve participants with acute myeloid leukemia (SAV) Phase II NCT05736965 AML, adult Drug: Selinexor Drug: Azacitidine Drug: Venetoclax SPEL as introductive treatment following immune-chemotherapy as consolidated therapy for R/R DLBCL With p53 and/or c-Myc expression Phase I–II NCT05498636 DLBCL Combination product: Selinexor combined with Prednisone, Etoposide, and Lenalidomide Real-world use of Selinexor, Daratumumab and dexamethasone in Chinese patients with multiple myeloma at first relapse Observational NCT05559788 Multiple Myeloma at First Relapse Clinical study of XPO1 inhibitor Selinexor combined With COPL in newly diagnosed advanced NK/T-cell lymphoma Phase II NCT05833893 nk/T-cell lymphoma Newly diagnosed advanced lymphoma Drug: XPO1 inhibitor Adaptive treatment for acute myeloid leukemia based on D14 MRD results Phase II NCT05736978 AML MRD Drug: Azacitidine Drug: Venetoclax Drug: Selinexor Hetrombopag in secondary prevention of XPO-1 inhibitor-induced thrombocytopenia in lymphoma Phase II NCT05969158 Chemotherapy-Induced Thrombocytopenia Drug: Hetrombopag Genotype-guided treatment in newly diagnosed PTCL (THEORY) Phase I–II NCT05675813 Peripheral T cell lymphoma Drug: CHOP + selinexor + 5-Azacitidine Drug: CHOP + duvelisib + 5-Azacitidine Drug: CHOP + chidamide + tislelizumab A study of evaluating the safety and efficacy of ATG-010, Bortezomib, and Dexamethasone (SVd) versus Bortezomib and dexamethasone (vd) in patients with relapsed or refractory multiple myeloma (RRMM) (BENCH) Phase III NCT04939142 Relapsed or refractory multiple myeloma Combination product: SVd (Selinexor + Bortezomib + dexamethasone) Combination Product: Vd (Bortezomib + dexamethasone) A study of ATG-010 in combination with Lenalidomide and Rituximab (R2) in adults with DLBCL and iNHL (SWATCH) Phase I–II NCT05265975 Diffuse large B-cell lymphoma indolent Non-Hodgkin lymphoma Drug: ATG-010 Drug: Lenalidomide Drug: Rituximab A study of evaluating the safety and efficacy of ATG-010 in relapsed/refractory diffuse large B-cell lymphoma (SEARCH) Phase II NCT03992339 Relapsed/refractory diffuse large B-cell lymphoma (DLBCL) Drug: ATG-010 60 mg, orally, twice weekly, each 4 week (28-day) a cycle A study of evaluating the safety and efficacy of ATG-010 combined with chemotherapy sequential With ATG-010 monotherapy maintenance in peripheral T- and NK/T-cell lymphoma (TOUCH) Phase I–II NCT04425070 Peripheral T-cell Lymphoma NK/T-cell Lymphoma Combination Product: ICE [ifosfamide + carboplatin + etoposide] Combination Product: GEMOX [gemcitabine + oxaliplatin] Combination Product: Tislelizumab SVRd for the treatment of newly diagnosed multiple myeloma patients presenting with extramedullary disease Phase II NCT05900882 Multiple myeloma Drug: Selinexor Drug: Bortezomib Drug: Lenalidomide Drug: Dexamethasone Novel combination therapy in the treatment of relapsed and refractory aggressive B-cell lymphoma Phase II NCT02436707 Lymphoma Drug: Ibrutinib Drug: Rituximab Drug: Gemcitabine Drug: Dexamethasone Drug: Cislatin Drug: Mesna Drug: Cyclophosphamide Drug: Etoposide Drug: G-CSF Drug: Selinexor Selinexol combined with dexamethasone in the treatment of CAEBV Phase III NCT05347381 CAEBV Drug: Selinexol and Dexamethasone Trial of safety and tolerability of oral Verdinexor (KPT-335) in healthy adults Phase I NCT02431364 Healthy Drug: Verdinexor Other: Placebo Eltanexor (KPT-8602) with Inqovi (Decitabine-Cedazuridine) in high-risk myelodysplastic syndromes Phase I–II NCT05918055 Myelodysplastic syndromes Drug: KPT-8602 Drug: Inqovi Eltanexor and Venetoclax in relapsed or refractory myelodysplastic syndrome and acute myeloid leukemia Phase I NCT06399640 Relapsed myelodysplastic syndrome Refractory myelodysplastic syndrome Acute myeloid leukemia Recurrent acute myeloid leukemia Refractory acute myeloid leukemia Drug: Eltanexor Drug: Venetoclax Procedure: bone marrow aspiration and biopsy Procedure: biospecimen collection A Phase 1 trial of a Novel XPO1 inhibitor in patients with advanced solid tumors Phase I NCT02667873 Solid tumors Drug: SL-801

XPO1 in cancer chemoresistance and overcoming drug resistance through SINE Drug resistance is a constant challenge for cancer patients and is often considered the main barrier to cure. Many cancer patients develop resistance to traditional chemotherapy or targeted therapies, thereby limiting further treatment options, which underlines the need for investigating and implementing combinational therapies in early stages of the disease [ 80 – 82 ]. In most cases, an initial positive response to one or multiple chemotherapies tends to diminish within several months to years, due to the emergence of secondary resistance mechanisms [ 13 , 34 ]. Among the various factors contributing to resistance, modification of nuclear proteins was found to play an important role [ 34 , 83 , 84 ]. Several investigators have shown that XPO1 overexpression facilitates the trigger of drug resistance mechanisms by mislocalization of proteins that function as drug targets [ 34 , 83 , 84 ]. The potential of SINE inhibitors to overcome the resistance upon systemic therapeutics was reported in various studies [ 13 , 85 ]. For instance, topoisomerases are important targets in many cancer chemotherapy regimens due to their distinct cellular functions [ 34 ]. Resistance to the topoisomerase II α inhibitor anthracycline is conferred by the misplacement of the transcription inhibitor E2F7 and the topoisomerase topo II α into the cytosol. Inhibition of XPO1 keeps E2F7 and topo II alpha in the cell nucleus, thereby restoring anthracycline sensitivity [ 34 , 86 ]. A significant correlation between XPO1 overexpression and platinum resistance in ovarian cancer patients has also been observed [ 87 ]. Targeting XPO1 by using KPT-185 or selinexor has demonstrated the ability to enhance tumor killing, inhibit cellular proliferation, and overcome platinum resistance [ 13 , 88 ].

In a recent publication, Wang et al . found that XPO1 was overexpressed in hepatocellular carcinoma (HCC) and was associated with worse survival outcomes [ 89 ]. When XPO1 was knocked down, it inhibited the migration and proliferation of HCC cells. It also reduced their resistance to the multi-kinase inhibitor sorafenib and effectively suppressed tumor growth [ 89 ].

Importantly, several studies demonstrated that XPO1 inhibition is effective independently of the TP53 mutational status [ 90 – 92 ]. Deng et al . found that TP53 mutations predict resistance to selinexor and that the resistance was overcome after combined treatment with selinexor and BET inhibitor in DLBCL [ 93 ], while in triple negative breast cancer preclinical model [ 94 ] the synergistic effect of selinexor with olaparib was confirmed regardless of the mutation status of BRCA1 [ 95 ]. However, in clinical practice, combining multiple drugs for intensive cancer treatment faces various challenges due to inconsistent pharmacokinetics among the therapeutic agents. The recent achievements in nanomedicine provide an innovative solution by encapsulating multiple drugs within a nano-carrier [ 96 , 97 ]. In a proof-of-concept study, researchers created a targeted therapy by inhibiting contemporary both XPO1 and ataxia telangiectasia mutated-Rad3-related (ATR). This treatment demonstrated extraordinary biocompatibility and enhanced the therapeutic effect, thus, providing a co-delivery strategy for liver cancer treatment [ 98 ]. These data indicate the urgent need for further investigations to enable more precise and personalized selinexor-based/combination cancer treatment strategies. However, until now, the functional and prognostic role of XPO1 in GI cancers remains somewhat unclear. In the next section we will summarize the current state of knowledge regarding XPO1 in the context of GI cancers.

The role of XPO1 in GI cancers

Esophageal cancer (EC)

Several studies have shown that both XPO1 mRNA and protein are overexpressed in EC [ 44 , 52 , 58 , 99 ]. Interestingly, the localization of XPO1 expression was altered in tumor compared to healthy tissue. While in healthy tissue XPO1 is solely expressed in the nucleus, in tumors, the expression was found in the nucleus and in the cytoplasm [ 58 ]. While, Van der Watt et al . described no correlation between XPO1 expression and tumor stage [ 58 ], Yang et al . reported a significant association between XPO1 overexpression and histological differentiation, lymph node metastasis, tumor size [ 52 ]. The inhibition of XPO1 resulted in decreased cell proliferation as well as apoptosis in various EC models [ 44 , 52 , 58 ]. Knockdown of XPO1 revealed a decrease in cellular viability and an induction of apoptosis [ 52 ]. Moreover, high XPO1 expression also impacts the survival of EC patients. According to data from The Cancer Genome Atlas (TCGA), patients with EC with high XPO1 mRNA expression have a significantly higher survival probability (Fig. 4 ). However, other studies have reported that XPO1 overexpression is associated with shorter OS and event-free survival [ 52 , 58 ]. Therefore, further studies are clearly needed to answer the question whether XPO1 is a prognostic marker in EC patients. Fig. 4 Data (mRNA & clinical data) was acquired from TCGA and cBioportal using the R packages TCGA biolinks and cbioportalR, respectively. Counts (mRNA) were normalized using the within & between lane normalization from the EDASeq package. Ideal cut-offs for XPO1 high and low tumors were determined iteratively using the survival package to choose the cut-off with the largest difference in survival. P values reported concern the difference in survival and are from a logrank-test. Differential gene expression was analyzed using the limma package – plots show the log2-fold change between groups on the x-axis and the log10(p-value) on the y-axis. The large blue dot represents XPO1. The results shown here are in whole based upon data generated by the TCGA Research Network: https://www.cancer.gov/tcga. (Abbreviations: TCGA: The Cancer Genome Atlas, COAD: colon adenocarcinoma, ESCA: esophageal carcinoma, STAD: stomach adenocarcinoma, LIHC: liver hepatocellular carcinoma, PAAD: pancreatic adenocarcinoma, CHOL: cholangiocarcinoma, LogFC: log2-fold change)

So far, only a few reports have investigated XPO1 inhibitors in clinical and preclinical studies in patients with EC (Table 1 ). In a multi-arm phase Ib study ( NCT02419495 ) 6 patients with advanced or metastatic solid tumors (two patients with EC) were included [ 100 ]. The safety and tolerability of selinexor was validated when given in combination with the standard chemotherapy drugs carboplatin and paclitaxel. One patient showed a partial response, whereas the other patient was excluded from the study before treatment start [ 100 ]. Two further clinical trials ( NCT02283359 , NCT02213133 ) have been investigating the safety and efficacy of selinexor in combination with standard of care chemotherapy in EC patients. The first trial ( NCT02283359 ) examined the effect of selinexor in combination with irinotecan in adenocarcinoma of stomach and distal esophagus. However, the study enrolled only three patients and was terminated without any results presented or published. The other study ( NCT02213133 ) investigated selinexor treatment in cancer patients with squamous cell histologies (including EC). However, none of the three EC patients enrolled completed the study.

Gastric cancer (GC)

Numerous studies have shown that XPO1 is overexpressed in GC samples compared to normal tissue [ 55 , 101 – 103 ]. A correlation between XPO1 expression and TNM stage, Her-2 status, metastasis and tumor progression has also been demonstrated. Moreover, a high XPO1 expression correlated with poor survival in GC [ 102 , 103 ]. For instance, Zhou et al. reported that 4-year survival rates were better for XPO1-low compared to XPO1-high expressors [ 103 ]. This is also confirmed by an analysis conducted using the TCGA. We observed that a higher XPO1 mRNA expression correlated significantly with a lower OS in GC patients compared to low XPO1 mRNA expressors (Fig. 4 ). Sexton et al . investigated the impact of inhibiting XPO1 mRNA via siRNA (siXPO1) and revealed that inhibiting XPO1 leads to a significant decrease of cancer cell proliferation and colony formation [ 101 ]. Thus, XPO1 might represent a potential target for GC patients.

In one of the first reports regarding the efficacy of SINEs in GC cell lines, Subhash et al . showed that selinexor had the greatest efficacy compared to other SINE components tested [ 55 ]. They demonstrated that selinexor activity is dependent on nuclear accumulation of p53. Nuclear retention of p53 is followed by an upregulation of p21, suggesting a restoration of p53 tumor suppressor function. In GC, in vivo and in vitro models, Sexton and colleagues established synergism of selinexor and other SINE compounds enhancing the efficacy of nab-paclitaxel [ 101 ]. They also demonstrated that SINE compounds can alter the expression of non-coding RNAs and reported a significant downregulation of oncogenic miR-33b-3p by SINE treatment.

We identified two studies involving patients with GC (Table 1 ). The first one, a phase I trial of selinexor ( NCT02078349 ) was designed to evaluate the safety, pharmacokinetics, and pharmacodynamics of selinexor. This study has been terminated, but the outcomes concerning the GC patients who were enrolled have not yet been published. The second trial ( NCT02283359 ) aimed to assess the efficacy of selinexor in combination with irinotecan for the treatment of GC and distal EC. Regrettably, none of the three GC patients enrolled have completed the study.

The lack of published data from these trials underscores the inherent challenges in progressing clinical research for GC patients. This emphasizes the critical need for ongoing efforts to elucidate the role of XPO1 in the pathogenesis GC, thereby providing essential insights for the development of future therapeutic strategies including XPO1 inhibitors.

Hepatocellular carcinoma (HCC)

Only a few studies have examined the influence of XPO1 expression in HCC. Zheng et al . reported that the expression of XPO1 is increased in HCC compared with normal liver tissue, and that inhibition with SINE compounds leads to growth inhibition and cell cycle arrest [ 105 ]. Similarly, Chen et al . showed that mRNA levels of XPO1 are significantly upregulated in HCC tissues compared to normal liver tissues [ 106 ]. XPO1 was associated with clinic pathological parameters, such as tumor grading, clinical stage and prognosis of HCC. High levels of XPO1 mRNA were more frequently observed in undifferentiated tumors and correlated with poor prognosis in HCC patients [ 106 , 107 ]. Data from TCGA indicate that a lower mRNA expression of XPO1 is associated with a worse OS compared to high expressors (Fig. 4 ).

The potential of selinexor and other SINE in HCC is yet to be explored. In a preclinical study [ 105 ], selinexor reduced the viability of HCC cell lines in vitro and inhibited tumor growth in HCC xenograft murine model. Treatment with selinexor up-regulated the expression of the TSPs p53 and p27 and the pro-apoptotic protein PUMA, and reduced the expression of the HCC promoting proteins c-Myc and c-Met [ 105 ].

A recent study investigated the effect of KPT-330 and the CDK4/6 inhibitor palbociclib in HCC cell lines [ 108 ]. Experiments have revealed that this combination treatment induces cellular senescence. In vivo, combination treatment with palbociclib and KPT-8602 (a structural analog of KPT-330) led to a significant reduction in tumor burden and improved survival in the HCC mouse model [ 108 ]. Deutzmann et al . demonstrated in vitro that after XPO1 inhibition with selinexor c-Myc-driven HCC showed an increase in apoptosis [ 109 ]. Moreover, XPO1 inhibition decreased the tumor volume in mice about 95% compared to control mice. Of note, Zhang et al . recently found elevated DBF4 expression in HCC that served as an independent prognostic factor [ 110 ]. Mechanistically, DBF4 complexed with CDC7 to form a DBF4-dependent kinase (DDK) and activated STAT3 signaling through XPO1-mediated nuclear export. Combining the DBF4 inhibitor XL413 with anti-PD-1 therapy suppressed HCC growth and prolonged survival in mice, demonstrating the involvement of XPO1 in this regulatory network and the potential of targeting DDK to enhance HCC immunotherapy.

A recent study combined selinexor with radiation in a preclinical model in human osteosarcoma and human HCCs [ 111 ]. The authors found enhanced radiation response in both cell lines by decreasing the intranuclear HIF-1α protein levels [ 111 ]. Nevertheless, more studies, especially clinical trials, are clearly necessary to understand the underlying mechanisms on irradiated cells and the significance of inhibition of DNA damage repair in cells treated with selinexor. Currently, only one clinical trial involving HCC patients and selinexor in combination with bevacizumab and atezolizumab is registered on ClinicalTrials.gov ( NCT05093608 ). However, this study was terminated prematurely, having enrolled just two participants, and consequently, no results have been reported yet.

Gallbladder cancer (GBC) & cholangiocarcinoma (CC)

Data regarding XPO1 in GBC and CC remains limited. To the best of our knowledge, only one study described the role of XPO1 in GBC. Zhao et al . reported that XPO1 mRNA expression was significantly increased in GBC tissue compared to corresponding non-cancerous tissues [ 112 ]. Moreover, a correlation of XPO1 expression and clinic-pathological data, such as lymph node metastasis and higher TNM stage, was observed. OS after curative surgery in patients with high XPO1 expression was significantly shorter compared with patients with low XPO1 levels [ 112 ]. The investigators also reported that inhibition of XPO1 by selinexor led to a significant reduction of cell proliferation and colony formation as well as an increase of apoptosis. The XPO1 inhibitor KPT-330 induced nuclear accumulation of p53 and activated the p53/mTOR signaling to regulate cell autophagy. The in vivo experiment showed that administration of selinexor suppressed the growth of GBC cells in a mouse xenograft model [ 112 ]. These results indicate selinexor as a potential treatment for GBC and highlights the need to further investigate its effects in humans.

Limited data on the role of XPO1 in CC is available [ 113 , 114 ]. According to the TCGA, higher XPO1 mRNA expression appears to be associated with better OS in CC patients compared to those with lower expression, although this difference is not statistically significant (Fig. 4 ). Bioinformatic analysis utilizing two public open accessible database revealed high XPO1 expression in various tumors including CC, which was associated with poor prognosis [ 114 ]. In CC, XPO1 expression is significantly increased compared to healthy controls. Moreover, XPO1 positively correlated with tumor grade and clinical stage [ 113 ]. Treatment with the XPO1 inhibitor KPT-330 demonstrated inhibition effects on CC cells [ 114 ]. Furthermore, XPO1 knockdown resulted in significantly impaired colony forming ability, reduced viability and G1 cell cycle arrest indicating apoptosis [ 113 , 114 ]. Conversely, overexpression of XPO1 led to a significantly higher proliferation of CC cells suggesting XPO1 promotes proliferation and progression. Consequently, XPO1 emerges as a potential novel target for the diagnosis, treatment, and prognosis of this cancer type [ 113 , 114 ]. However, currently no clinical trial was initiated for patients with CC.

Pancreatic ductal adenocarinoma (PDAC)

In 2009, Huang et al . found that XPO1 is overexpressed in over 55% of PDACs compared to normal tissue [ 10 , 69 ]. High XPO1 levels were linked to larger tumor size, lymph node involvement, metastasis, and poorer OS and PFS, suggesting XPO1 as a potential prognostic marker for PDACs [ 115 ]. Azmi et al . showed that XPO1 regulates the shuttling of mature microRNAs (miRNAs), including tumor-suppressive miR-145 [ 17 ]. Inhibiting XPO1 upregulates miR-145, which downregulates its target signaling pathways, thus inhibiting PDAC cell proliferation and migration. The lack of miR-145 in PDAC cells contributes to the cancer's aggressiveness, and XPO1 inhibition mitigates this by increasing miR-145 levels and suppressing its target pathways [ 17 ].

Saulino et al . described that in the majority of PDACs (86%) a positive staining for XPO1 was detected [ 116 ]. The localization of the XPO1 expression was mainly in the nucleus. A positive correlation between XPO1 and survivin expression was observed. In a separate study, researchers examined the expression of XPO1 in tissues from normal, primary, and metastatic patients [ 117 ]. The findings revealed a notable rise in XPO1 expression as the tumor stage advanced. Additionally, a significant correlation was observed between pathological lymph node status and the expression of XPO1. A shorter OS was observed for high vs low XPO1 expressors [ 117 ]. This result was confirmed by another study, where survival was also shorter in XPO1 high compared to the XPO1 low group [ 118 ]. These contradictory findings from the TCGA indicate that high expression of XPO1 is significantly associated with extended OS in PDAC patients compared to patients with low XPO1 expression (Fig. 4 ). Altogether, several studies have shown that overexpression of XPO1 in PDACs is associated with poor prognosis, most likely due to the inactivation of TSPs [ 17 , 115 – 118 ]. Thus, it would be very important to analyze how XPO1 expression might predict prognosis and response to clinical SINE compounds. So far, several studies reported promising pre-clinical data using XPO1 inhibitors in PDACs. Azmi et al . reported that SINE compounds (KPT-185, KPT-127, KPT-205, and KPT-227) blocked PDAC cell proliferation, induced apoptosis, and retained important TSPs, such as p53, p73, FOXO and prostate apoptosis response-4 (PAR-4) in the nucleus [ 16 ]. Moreover, selinexor disrupted the XPO1-PAR-4 interaction and activated PAR-4 signaling, one of the critical pro-apoptotic pathways in PDAC [ 119 , 120 ], resulting in enhanced apoptosis. The oral administration of the drug in mice reduced the growth of xenograft tumors without major toxicities revealing a promising novel treatment in PDAC [ 16 ].

Further, the combined use of SINE and gemcitabine in PDACs was investigated and their combination resulted in a synergistic effect, drastically reducing the growth of PDAC cells in vitro and reducing tumor volume in vivo in an orthotopic mouse model, through depletion of the anti-apoptotic proteins and induction of apoptosis [ 121 ]. Moreover, selinexor in combination with gemcitabine and nab-paclitaxel revealed the suppression of spheroid formation in cancer stem cells (CSC), induced spheroid disintegration and blocked CSC growth in a xenograft model [ 72 ]. In line with these results, another study showed that the combined treatment of selinexor with gemcitabine and paclitaxel resulted in a prolonged survival time of mice [ 122 ].

Since the tumor progression from normal ductal epithelium to PDAC requires sequential genetic alterations initiated by the KRAS mutation, and considering that nearly 90% of conventional PDACs show an oncogenic KRAS mutation, the selinexor effect was analyzed in combination with KRAS G12C inhibitors in a further PDAC model [ 123 ]. Khan et al . demonstrated that in KRAS G12C inhibitor-resistant cells, the addition of selinexor to the KRAS G12C inhibitor significantly decreased cell colony formation in vitro and inhibited tumor formation in mice [ 123 ]. These studies highlight novel combination therapies for PDAC and provide a founded rationale for the use of selinexor in a clinical setting to improve patient outcomes and to prevent the development of resistance to the standard monotherapy. Currently, two clinical trials are investigating the utilization of selinexor and its potential for innovative combination therapeutic strategies for PDAC patients (Table 1 ). In a phase I trial ( NCT02178436 ), nine patients with metastatic PDAC were treated with the combination of selinexor, gemcitabine and nab-paclitaxel and a partial response and a stable disease were observed in two PDAC patients [ 72 ]. A phase IB study is currently ongoing ( NCT02419495 ) with the objective of assessing the safety profile of selinexor when used in combination with various established chemotherapy or immunotherapy in patients with advanced malignant solid neoplasms, including colorectal cancer, EC and PDAC. Nonetheless, the cohort size of PDAC patients enrolled in this trial is still very low.

Despite the encouraging outcomes derived from pre-clinical investigations and the initial clinical phase, further validation of these results, alongside comprehensive studies to evaluate the safety and therapeutic efficacy of selinexor in PDAC patients, are still pending.

Colorectal "Cancer" instead of "carcinoma" (CRC)

Colorectal cancer (CRC) is another tumor in which XPO1 is frequently overexpressed. However, data on the role of XPO1 overexpression in CRC remains unclear [ 56 , 124 , 125 ]. Elevated XPO1 activity can increase oncogenic activity through mislocalization of proteins like p27, p53 and survivin and, thus dysfunction in cancer cells and a general association with poor outcome [ 56 , 125 ]. According to the TCGA, high mRNA expression of XPO1 leads to a significantly better OS compared to low expression of XPO1 in CRC patients (Fig. 4 ). No correlation was observed between XPO1 overexpression and tumor size [ 56 ]. XPO1 was strongly expressed in more than 50% of samples ( n = 40). Especially nuclear expression was detected in more than half and cytoplasmic expression in 37% [ 56 ]. Inhibition of XPO1 leads to impaired proliferation in 2D and 3D cell cultures [ 56 , 124 ]. Moreover, after inhibition of XPO1, apoptosis was induced in these cells [ 56 , 124 , 126 ]. Inoue and colleagues reported that cell cycle arrest was due to expression of specific DNA damage response (DDR) genes [ 124 ]. Conversely, it has been demonstrated that XPO1 overexpression and loss of p53 was mostly observed in poorly differentiated tumors, advanced tumor stage and lymph node metastasis [ 56 , 125 ].

XPO1 is also responsible for the transportation and subcellular distribution of survivin between the nucleus and cytoplasm [ 104 ]. Survivin is an inhibitor of the apoptosis protein (IAP) and is overexpressed in most human tumors [ 104 , 127 ]. Survivin is usually undetectable or expressed at very low levels in normal cells and mainly produced by cancer cells, therefor making it a putative tumor marker [ 127 ]. A significant positive correlation between XPO1 and survivin expression was seen in CRC [ 104 ]. Overexpression of survivin in cytoplasm may protect cancer cells by inhibiting apoptosis and thus promotes tumor progression [ 104 ].

Several preclinical and clinical studies have demonstrated the therapeutic potential of XPO1 inhibition mediated by selinexor in CRC. Aladhraei et al . reported that selinexor reduced cancer cells proliferation in a dose- and time-dependent manner and significantly inhibited-colon cancer growth in vitro [ 56 ]. A synergistic effect was observed when combining selinexor with the proteasome inhibitor bortezomib on wild-type p53 CRC cells, as reported by Wu et al . [ 128 ]. The results were confirmed in vivo , indicating that p53 is a major mediator of the synergistic cytotoxic effect of bortezomib and selinexor.

Moreover, selinexor synergistically enhanced the radiation response in preclinical models of CRC [ 129 ]. Both in CRC cell lines and xenograft tumor models, combination treatment of selinexor and radiotherapy resulted in a decrease of proliferation and reduction of the tumor size by promoting nuclear survivin accumulation and induction of apoptosis [ 129 ].

Building on the foundation of these promising preclinical studies, a path has been established for the initiation of clinical trials targeting CRC patients. Employing the previously delineated search parameters, our investigation on ClinicalTrials.gov identified seven clinical studies involving CRC patients (Table 1 ). In a phase I trial ( NCT01607905 ), the safety and efficacy of selinexor were assessed in a cohort of 189 pretreated tumor patients, including 59 CRC patients [ 130 ]. The phase II dose of selinexor established at 35 mg/m2 and administered bi-weekly was deemed safe and well-tolerated [ 130 ]. Notably, selinexor showed a disease control rate of 44% [ 130 ]. It was established based on this study, that selinexor dosing interruptions alone are likely sufficient for treating selinexor-induced thrombocytopenia [ 131 ]. The treatment of selinexor in combination with multiple standard chemotherapy or immunotherapy agents is under investigation in a phase IB trial ( NCT02419495 ) in patients with advanced malignancies, including CRC patients. Another clinical trial ( NCT04854434 ) is currently investigating the efficacy and safety of selinexor, both as a monotherapy and in conjunction with pembrolizumab, in participants with advanced or metastatic colorectal cancer. Additionally, the pharmacokinetics and pharmacodynamics of selinexor have been validated in Asian populations through a further phase I trial ( NCT02078349 ). This study involved screening patients for approximately 2800 COSMIC mutations across 50 cancer genes, including those in the RAS/RAF and PIK3CA/AKT/mTOR pathway. The results indicated that 40% of CRC patients harboring mutations in the RAS/AKT pathway achieved a disease control rate exceeding three months, in contrast to 12.5% of CRC patients with no mutations in the respective genes [ 132 ].

Lastly, the investigation of safety, tolerability, and efficacy of KPT-8602 (eltanexor), another SINE, is currently ongoing. This study ( NCT02649790 ) includes participants with relapsed/refractory cancer indications, among them also patients with metastatic CRC.

In light of these findings, it remains crucial to advance additional clinical investigations in CRC, aiming to validate the promising therapeutic potential of selinexor and refine treatment approaches for better patient outcomes.

Gastrointestinal stromal tumors (GIST) & neuroendocrine neoplasia (NEN) of the gastrointestinal tract (GIT)

The relevance of nuclear exporters in GIST or gastroenteropancreatic NEN is unclear and only a handful of research articles have been published on this topic. Nakayama et al . investigated the efficacy of selinexor in vitro and in vivo using 17 cell lines and 9 sarcoma xenograft models including GIST [ 90 ]. In GIST cells with cKIT mutations, selinexor induced G1-arrest independent of attenuation of phosphorylation of KIT, AKT, or MAPK, indicating the potential of selinexor and thereby also highlighting the need for further investigation, potentially also for the use of selinexor in clinical trials targeting various sarcoma subtypes. A further clinical trial ( NCT04138381 ) is analyzing the maximum tolerated dose and the recommended phase II doses of selinexor in combination with imatinib among unresectable and/or metastatic GIST patients with prior failure to at least imatinib for advanced/metastatic disease. However, there are no data regarding the use of selinexor in GIST patients.

Regarding NEN and XPO1, the list of publications is even more limited. The ten-eleven translocation (TET) protein family influences epigenetics, initiates demethylation pathways and is associated with tumorigenesis [ 133 , 134 ]. In 2018, Barazheghi et al . showed a loss of nuclear localization of TET2 in small intestine neuroendocrine tumors (SI-NETs) and demonstrated in a cell culture experiment with SI-NET cell lines (KRJ-I and CNDT2.5) that incubation of these cell lines with leptomycin B led to a retention of TET2 in the nucleus and a reduction of it in the cytoplasm [ 135 ], implicating XPO1 as a potential therapeutic target.

Conclusion

Disruption of nuclear export processes compromises various cellular functions crucial for inhibiting oncogenesis and restraining tumor growth. Extensive investigations have been undertaken to identify and characterize the pivotal molecular entities governing the bidirectional exchange between the nucleus and cytoplasm [ 4 ]. These endeavors have yielded invaluable insights, laying the groundwork for targeted drug development initiatives aimed at modulating key factors orchestrating nuclear export, prominently exemplified by XPO1, as delineated in this review. The emergent body of knowledge not only elucidates novel facets of cancer pathogenesis but also revolutionizes therapeutic paradigms, facilitating the design of precision medicines tailored to individual patient profiles. Selective inhibition of XPO1 holds promise in rectifying intracellular imbalances, thereby impeding tumorigenesis. The versatility of XPO1 inhibitors is underscored by their capacity to synergistically potentiate the anticancer efficacy of extant therapies and potentially surmount resistance to conventional modalities, thereby fostering improved clinical outcomes [ 121 , 136 ].

The preeminent XPO1 inhibitor under investigation is selinexor, which has shown promising outcomes in both hematologic and solid malignancies. While other SINEs, such as verdinexor, eltanexor, KPT-9274, and KPT-8602, are undergoing clinical trials at various stages, the focus on GI tumors in these trials remains limited. This paucity of clinical research poses a barrier to comprehensively understanding selinexor's efficacy, safety, and optimal dosing and combination regimens in the realm of GI malignancies, necessitating further targeted investigation. The establishment of ideal conditions for achieving maximal anti-tumor effects with minimal toxicity is paramount for delineating the role of SINEs in GI cancers. This imperative is underscored by the recognition that treatment optimization will necessitate tailored regimens based on the utilization of XPO1 inhibitors across diverse patient cohorts. Furthermore, the identification of specific prognostic markers holds potential for discerning patient subsets likely to derive the greatest benefit from XPO1 inhibition. Achieving this objective mandates a nuanced comprehension of the genetic and molecular profiles characterizing tumors, facilitating the precision matching of patients with their most efficacious treatment modalities.

Abbreviations

Ataxia telangiectasia mutated-Rad3-related

B-cell receptor

Bruton tyrosine kinase

Cholangiocarcinoma

Classical Hodgkin's lymphoma

Lymphocytic leukemia

Colorectal cancer

Chromosome region maintenance 1

Cancer stem cells

Disease control rates

DBF4-dependent kinase

DNA damage response

Diffuse large b-cell lymphoma

Esophageal cancer

Epidermal growth factor receptor

Esophageal squamous cell carcinoma

Gallbladder cancer

Gastric cancer

Gastrointestinal

Gastrointestinal tract

Gastrointestinal stromal tumors

Hepatocellular carcinoma

Inhibitor of the apoptosis protein

Multiple myeloma

MicroRNAs

Nuclear export signal

Neuroendocrine neoplasia

Nuclear localization signal

Nuclear pore complex

Overall survival

Prostate apoptosis response-4

Pancreatic ductal adenocarcinoma

Progression-free survival

Primary mediastinal diffuse large b-cell lymphoma

Ras-related nuclear protein

GTPase-activating protein

Regulator of chromosome condensation 1

Selective inhibitors of nuclear export

Small intestine neuroendocrine tumors

Ten-eleven translocation

Tumor suppressor proteins

Exportin-1

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Viktorija Sokolova, Rebecca Gruber, Lorenz M. Pammer, Daniel Neureiter, and Andreas Seeber have contributed equally.

Authors' contributions

V.S., R.G., L.M.P., F.K., E.K., A.A., R.P., M.G., S.O., D.N. and A.S. wrote the main manuscript text and prepared the figures and tables. All authors read and approved the final manuscript.

Funding

The authors declare that no funds, grants, or other support were received during the preparation of this manuscript.

Data Availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Ethical approval

Not applicable.

Consent to participate

Not applicable.

Consent to publish

Not applicable.

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