Inhibitor Of Nuclear Export Research Articles

Sequential Administration of Selinexor and CAR-T Therapy in Relapsed/ Refractory Multiple Myeloma

Introduction: Selinexor is a novel, oral selective inhibitor of nuclear export (SINE) that binds to exportin 1 and exhibits anti-tumor activity by impairing nuclear export of proteins including oncogenes and tumor suppressor proteins and is approved for use in patients with relapsed refractory multiple myeloma(RRMM). Anti-BCMA directed CAR-T therapy for patients with relapsed/refractory multiple myeloma (RRMM) is a promising new class of therapy, which has shown a high level of efficacy. Sequential administration of selinexor followed by CD19 CAR-T has shown enhanced efficacy in human phase II trials and animal models of human non-hodgkin lymphoma(Stadel et al., 2022). In this retrospective single institutional study, we report outcomes of patients with RRMM who were treated with Selinexor based regimen prior to apheresis for CAR-T therapy. Methods: We conducted a retrospective study on an IRB-approved protocol for all patients who were treated with Selinexor based regimen immediately prior to apheresis as a prior line of therapy at Hackensack University Medical Center between June 2015 and July 2022. Demographic characteristics, molecular studies, treatment and response information were recorded and included in the study. Response to CAR-T was assessed by the treating physician per International Myeloma Working Group (IMWG) criteria. Survival analysis was performed using the Kaplan-Meier method including PFS and Overall survival (OS). Results: Between September 9, 2021, and April 3, 2023, 7 patients received CAR-T who were treated with Selinexor immediately prior to apheresis. The median age was 65.7 years (range: 55.1-77.1 years). Patients had a median of 6 (range: 4-10) lines of therapy (LOT) prior to CAR-T. 5 out of the 7 patients had double hit myeloma (all 5 with 17p and one other high risk). Four patients were treated with selinexor, carfilzomib and dexamethasone; two patients were treated with selinexor, daratumumab and dexamethasone and one patient was treated with selinexor, pomalidomide and dexamethasone. Four patients received Idecabtagene vicleucel (ide-cel) and three patients received ciltacabtagene autoleucel (cilta-cel). ORR was 100% with all 7 pts achieving very good partial response or better (>=VGPR). 2 patients had bone marrow biopsies that confirmed MRD -ve sCR in both patients. None of the patients have progressed so far, although median follow-up is short at 5.6 months. All patients had hematologic toxicities, 4/7 with grade III anemia (57.1%), 3/7 (42.8%) with grade or higher thrombocytopenia and 4/7 (57.1%) had grade 3 neutropenia. 2 of 7 patients had prolonged cytopenia for >6 months because of pre-existing underlying diagnoses of CCUS and MDS. 5 out of 7 patients had grade 1 Cytokine release syndrome (CRS). The other two patients did not experience CRS. Time of CRS onset was variable 2-10 days. No ICANS or infectious complications were observed. Conclusions: These results suggest that sequential use of Selinexor and CART in high risk RRMM may be an effective treatment strategy to provide deep and durable responses. The findings of our study are promising although it is limited by a small sample size and short follow-up. Further investigation in a larger study and longer follow up would be important to confirm our findings.

Impacting T-cell fitness in multiple myeloma: potential roles for selinexor and XPO1 inhibitors.

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. Reduced T-cell fitness not only diminishes immune defenses, increasing patient susceptibility to opportunistic infections, but can impact effectiveness MM therapy effectiveness, bringing into focus sequencing strategies that could modulate T-cell fitness and potentially optimize overall benefit and clinical outcomes. Certain targeted agents used to treat MM, such as selective inhibitors of nuclear export (SINE) compounds, have the potential to mitigate T-cell exhaustion. Herein referred to as XPO1 inhibitors, SINE compounds inhibit the nuclear export protein exportin 1 (XPO1), which leads to nuclear retention and activation of tumor suppressor proteins and downregulation of oncoprotein expression. The XPO1 inhibitors selinexor and eltanexor reduced T-cell exhaustion in cell lines and animal models, suggesting their potential role in revitalizating these key effector cells. Additional clinical studies are needed to understand how T-cell fitness is impacted by diseases and therapeutic factors in MM, to potentially facilitate the optimal use of available treatments that depend on, and impact, T-cell function. This review summarizes the importance of T-cell fitness and the potential to optimize treatment using T-cell engaging therapies with a focus on XPO1 inhibitors.

4-Octyl itaconate reduces influenza A replication by targeting the nuclear export protein CRM1.

Itaconate derivates, as well as the naturally produced metabolite, have been proposed as antivirals against influenza virus. Here, the mechanism behind the antiviral effects of exogenous 4-octyl itaconate (4-OI), a derivative of itaconate, against the influenza A virus replication is demonstrated. The data indicate that 4-OI targets the cysteine at position 528 of the CRM1 protein, resulting in inhibition of the nuclear export of viral ribonucleoprotein complexes in a similar manner as previously described for other selective inhibitors of nuclear export. These results postulate a mechanism not observed before for this immuno-metabolite derivative. This knowledge is helpful for the development of derivatives of 4-OI as potential antiviral and anti-inflammatory therapeutics.

Selinexor for the treatment of recurrent or metastatic salivary gland tumors: Results from the GEMS-001 clinical trial.

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). 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. The primary endpoint was objective response rate. Secondary endpoints included progression-free survival (PFS) and prevalence of druggable alterations across SGT. One hundred patients were enrolled in GEMS-001 and underwent genomic and immunohistochemistry profiling. A total of 21 patients who lacked available matched therapies were treated with selinexor. SGT subtypes (WHO classification) included adenoid cystic carcinoma (n = 10), salivary duct carcinoma (n = 3), acinic cell carcinoma (n = 2), myoepithelial carcinoma (n = 2), carcinoma ex pleomorphic adenoma (n = 2) and other (n = 2). Of 18 evaluable patients, stable disease (SD) was observed in 17 patients (94%) (SD ≥6 months in 7 patients (39%)). However, no objective responses were observed. The median PFS was 4.9 months (95% confidence interval, 3.4-10). The most common treatment-related Grade 1-2 adverse events were nausea [17 patients (81%)], fatigue [16 patients (76%)], and dysgeusia [12 patients (57%)]. Most common treatment-related Grade 3-4 adverse events were hyponatremia [3 patients (14%)], neutrophil count decrease [3 patients (14%)] and cataracts [2 patients (10%)]. No treatment-related deaths were observed. Although tumor reduction was observed across participants, single agent selinexor anti-tumor activity was limited.

Development of chalcone-like derivatives and their biological and mechanistic investigations as novel influenza nuclear export inhibitors

Concerning the emergence of resistance to current anti-influenza drugs, our previous phenotypic-based screening study identified the compound A9 as a promising lead compound. This chalcone analog, containing a 2,6-dimethoxyphenyl moiety, exhibited significant inhibitory activity against oseltamivir-resistant strains (H1N1 pdm09), with an EC50 value of 1.34 μM. However, it also displayed notable cytotoxicity, with a CC50 value of 41.46 μM. Therefore, compound A9 was selected as a prototype structure for further structural optimization in this study. Initially, it was confirmed that the substituting the α,β-unsaturated ketone with pent-1,4-diene-3-one as a linker group significantly reduced the cytotoxicity of the final compounds. Subsequently, the penta-1,4-dien-3-one group was utilized as a privileged fragment for further structural optimization. Following two subsequent rounds of optimizations, we identified compound IIB-2, which contains a 2,6-dimethoxyphenyl- and 1,4-pentadiene-3-one moieties. This compound exhibited inhibitory effects on oseltamivir-resistant strains comparable to its precursor (compound A9), while demonstrating reduced toxicity (CC50 > 100 μM). Furthermore, we investigated its mechanism of action against anti-influenza virus through immunofluorescence, Western blot, and surface plasmon resonance (SPR) experiments. The results revealed that compound IIB-2 can impede virus proliferation by blocking the export of influenza virus nucleoprotein. Thusly, our findings further emphasize influenza nuclear export as a viable target for designing novel chalcone-like derivatives with potential inhibitory properties that could be explored in future lead optimization studies.

Selinexor in Combination with Decitabine Attenuates Ovarian Cancer in Mice.

High-grade serous ovarian cancer is a lethal gynecologic disease. Conventional therapies, such as platinum-based chemotherapy, are rendered inadequate for disease management as most advanced disease patients develop resistance to this therapy and soon relapse, leading to poor prognosis. Novel immunotherapy and targeted therapy are currently under investigation as treatment options for ovarian cancer, but so far with little success. Epigenetic changes, such as aberrant DNA methylation, have been reported in resistance to platinum-based therapy. Decitabine is a hypomethylating agent which is effective against platinum-resistant disease and also exhibits several anti-tumor immune functions. Selinexor is a selective inhibitor of nuclear protein export. It restored platinum sensitivity in patient-derived ovarian cancer cell lines and is currently in clinical trials for the treatment of platinum-resistant ovarian cancer. We hypothesized that these two agents used in combination could elicit more potent anti-tumor immune responses in vivo than either agent used alone. These studies were designed to investigate the efficacy of these two agents used in combination to treat ovarian cancer by assessing murine models for changes in disease pathology and in anti-tumor responses. Decitabine priming followed by selinexor treatment significantly limited ascites formation and tumor size. This combination of agents also promoted T cell effector function as measured by granzyme B secretion. Treatment of mice with decitabine and selinexor led to the significant release of a broader range of macrophage and T cell cytokines and chemokines above control PBS and vehicle and above decitabine or selinexor treatment alone. These results reveal crucial information for the design of clinical trials which may advance therapy outcomes in ovarian cancer.

Nuclear translocation of Axl contributes to the malignancy of oral cancer cells

Background/purposeDysregulation of receptor tyrosine kinases is implicated in cancer development. This study aimed to investigate the nuclear translocation of Axl, a membrane protein and receptor tyrosine kinase in cancer malignancy. Materials and methodsWe examined Axl's entry into the cell nucleus and validated it with the nuclear export inhibitor leptomycin. Transfection experiments with mutated nuclear localization signals were conducted to assess the impact of reduced nuclear Axl levels on cancer cell malignancy. Additionally, we evaluated the effects of decreased nuclear Axl on sensitivity to radiation and cisplatin, a chemotherapeutic drug. ResultsIn the present study, we observed nuclear translocation of Axl in cancer cells. Reducing nuclear Axl levels led to a decrease in cancer cell malignancy. This nuclear translocation was further validated using a nuclear export inhibitor, leptomycin. Additionally, transfection experiments with mutated nuclear localization signals confirmed the functional significance of Axl's nuclear localization. Notably, decreased nuclear Axl levels also increased the sensitivity of cancer cells to radiation and cisplatin treatment. ConclusionThis study suggests that Axl's nuclear translocation plays a significant role in cancer malignancy. Targeting Axl's nuclear localization could offer a potential strategy to inhibit cancer progression and improve the efficacy of radiation and chemotherapy treatments.

Therapeutic targeting of nuclear export and import receptors in cancer and their potential in combination chemotherapy.

Systemic modalities are crucial in the management of disseminated malignancies and liquid tumours. However, patient responses and tolerability to treatment are generally poor and those that enter remission often return with refractory disease. Combination therapies provide a methodology to overcome chemoresistance mechanisms and address dose-limiting toxicities. A deeper understanding of tumorigenic processes at the molecular level has brought a targeted therapy approach to the forefront of cancer research, and novel cancer biomarkers are being identified at a rapid rate, with some showing potential therapeutic benefits. The Karyopherin superfamily of proteins is soluble receptors that mediate nucleocytoplasmic shuttling of proteins and RNAs, and recently, nuclear transport receptors have been recognized as novel anticancer targets. Inhibitors against nuclear export have been approved for clinical use against certain cancer types, whereas inhibitors against nuclear import are in preclinical stages of investigation. Mechanistically, targeting nucleocytoplasmic shuttling has shown to abrogate oncogenic signalling and restore tumour suppressor functions through nuclear sequestration of relevant proteins and mRNAs. Hence, nuclear transport inhibitors display broad spectrum anticancer activity and harbour potential to engage in synergistic interactions with a wide array of cytotoxic agents and other targeted agents. This review is focussed on the most researched nuclear transport receptors in the context of cancer, XPO1 and KPNB1, and highlights how inhibitors targeting these receptors can enhance the therapeutic efficacy of standard of care therapies and novel targeted agents in a combination therapy approach. Furthermore, an updated review on the therapeutic targeting of lesser characterized karyopherin proteins is provided and resistance to clinically approved nuclear export inhibitors is discussed.

Discovery of ligustrazine and chalcone derivatives as novel viral nucleoprotein nuclear export inhibitors against influenza viruses.

Influenza viruses pose a significant threat to human health worldwide due to seasonal epidemics and occasional global pandemics. These viruses can cause severe upper respiratory tract infections that contribute to high morbidity and mortality rates. The emergence of drug-resistant influenza viruses has created the need for the development of novel broad-spectrum antivirals. Here, we present a novel anti-influenza agent with new targets and mechanisms of action to address this problem. Our findings led to the discovery of a novel influenza virus inhibitor, a ligustrazine derivative known as A9. We have found that it exhibits broad-spectrum antiviral properties against influenza A and B viruses (IAV and IBV, respectively), including oseltamivir-resistant strain. Through multiple bioassays such as time-of-addition assay, indirect immunofluorescence assay, and nuclear-cytoplasmic fractionation assay, we demonstrated that A9 inhibits the nuclear export of the viral ribonucleoprotein (vRNP). Furthermore, escape mutant analyses and affinity studies determined by surface plasmon resonanceindicated that A9 specifically targets the nucleoprotein.In addition, four chalcone derivatives developed from A9 (B14, B29, B31, and B32), were found to effectively inhibit the replication of influenza virus through the same mechanism of action. In this manuscript we highlight A9 and its four derivatives as potential leads for the treatment of IAV and IBV infections, and their unique and novel mechanism of action probable benefit the field of anti-influenza drug discovery.

Discovery of Eriodictyol as Putative Exportin-1 Inhibitor for Non-small Cell Lung Cancer Therapy

Exportin-1, the ubiquitous nuclear protein transporter, is widely confirmed as an active chemotherapeutic target in non-small cell lung cancer conditions, while Juglans mandshurica is a well-studied anticancer plant in some lung cancer cell lines. We intend to find a novel exportin-1 inhibitor from Juglans mandshurica with better potential, tolerability and pharmaco-dynamo-kinetic properties than the current selective inhibitors of nuclear export in non-small cell lung cancer treatment. OSIRIS DataWarrior, along with Glide standard precision docking, and other Glide modules were employed for compound properties exploration, docking simulations, free energy calculations against exportin-1; density functional theory analysis of the compounds were carried out to estimate their electronic stability, while web-based SWISSADME was employed for ADMET and synthetic accessibility evaluations. This study reveals eriodictyol as having higher binding free energy (-40 kcal/mol) than that of standard (-39.56 kcal/mol) in exportin-1 active site, better synthetic accessibility score (3.15 versus 3.29), high GI absorption, non-blood brain barrier permeant, lacks Brenk and PAINS alert, obeying Lipinski’s, Ghose’s, Veber’s, Egan’s, and Muegge’s rule of drug-likeness and lead-likeness as well as non-cytotoxic to HepG2 cells. We therefore found eriodictyol as a lead-like, non-toxic exportin-1 inhibitor with good predictive stability and pharmacokinetic potential and thus provided data for further validation of eriodictyol as a candidate exportin-1 inhibitor in both preclinical and clinical studies involving lung cancer therapy.

Dual targeting of protein translation and nuclear protein export results in enhanced antimyeloma effects.

Selinexor (KPT-330) is a small molecule inhibitor of XPO1, which mediates the transport of tumor suppressor proteins, oncogene messenger RNAs, and other proteins involved in governing cell growthfrom the cell nucleus to the cytoplasm. It is overexpressed in many cancer types. Because eukaryotic translation initiator factor 4E (eIF4E) plays a critical role in protein translation in cancer cells in multiple myeloma (MM), we evaluated the effectiveness of combined inhibition of protein translation and nuclear export in MM. Selinexor, an inhibitor of nuclear protein export, dose-dependently decreased eIF4E, IKZF1, and c-MYC protein levels. Using a doxycycline-inducible-pLKO-Tet-On vector, knockdown of eIF4E significantly enhanced the antiproliferative effects of selinexor, sensitized resistant MM cells to selinexor, and increased apoptosis in MM cells. Immunofluorescent analysis of MM cells showed that the combined treatment increased the localization of residual eIF4E to the nucleus compared with selinexor-only treatment. The overexpression of eIF4E at least partially rescued the effects of selinexor in MM cells by reducing G1 cell cycle arrest and increasing the selinexor-IC50 10-fold. Moreover, the combination of selinexor with pharmacologic inhibitors of protein translation showed synergistic anti-MM effects. These results suggest a synergistic anti-MM effect of selinexor combined with eIF4E inhibitors invitro. Our work provides a better understanding of the potential mechanism of resistance to selinexor and a rationale for combining selinexor with eIF4E inhibitors for the treatment of MM.

LGG-16. NOVEL COMBINATION THERAPIES FOR PEDIATRIC LOW-GRADE GLIOMA AND CHARACTERIZATION OF THE UNDERLYING CELL DEATH MECHANISMS

Abstract BACKGROUND The majority of pediatric low-grade gliomas (pLGGs) harbor a MAPK/ERK pathway overactivating alteration, making them suitable for MAPK-targeted therapies such as MEK inhibition. However, MEK inhibitor treatment alone is in most cases not sufficient to induce complete response, and a rapid rebound of the tumor is the consequence after withdrawal of the therapy. METHODS To identify novel cytotoxic drug combinations, we screened 89 clinically relevant drugs in combination with the MEK inhibitors trametinib and binimetinib. We assessed the regression of cultured 3D microtumors of patient-derived BT40 and BT314 cells, both harboring a BRAFV600E mutation. Depending on the inducible expression of SV40 large T antigen, the BT314 model can reflect two states, proliferation and oncogene-induced senescence. The area of spheroids was measured both in brightfield and with the fluorescent dye TMRE (mitochondrial polarization) at the start and the end of the treatment (6 days). Moreover, metabolic activity was determined through bulk ATP measurement. Drug hit combinations were further analyzed for the successful induction of cell death using high-content microscopy (HCM) imaging and enzymatic caspase activity assays. The microscopic readouts included Hoechst 33342 for the detection of nuclear morphology, BODIPY for sensitizing lipid peroxidation and CM-H2DCFDA as a general oxidative stress indicator. The images were analyzed with the automated image analysis program CellProfiler and the machine learning application CellProfiler Analyst. RESULTS The screening identified the following drug hits: navitoclax (BCL-2 family inhibitor), BRAF inhibitor dabrafenib, mTOR inhibitor everolimus and selinexor, a selective inhibitor of nuclear export. All drugs increased apoptotic cell death and ROS levels at clinically achievable drug concentrations, except the mTOR inhibitors. These results are currently validated in vivo with BT40 zebrafish embryo xenograft models. CONCLUSION Combinations of MEK inhibitors with navitoclax, dabrafenib or selinexor resulted in sufficient apoptosis to induce regression of pLGG microtumors in vitro.

Nsp14 of SARS-CoV-2 inhibits mRNA processing and nuclear export by targeting the nuclear cap-binding complex.

To facilitate selfish replication, viruses halt host gene expression in various ways. The nuclear export of mRNA is one such process targeted by many viruses. SARS-CoV-2, the etiological agent of severe acute respiratory syndrome, also prevents mRNA nuclear export. In this study, Nsp14, a bifunctional viral replicase subunit, was identified as a novel inhibitor of mRNA nuclear export. Nsp14 induces poly(A)+ RNA nuclear accumulation and the dissolution/coalescence of nuclear speckles. Genome-wide gene expression analysis revealed the global dysregulation of splicing and 3'-end processing defects of replication-dependent histone mRNAs by Nsp14. These abnormalities were also observed in SARS-CoV-2-infected cells. A mutation introduced at the guanine-N7-methyltransferase active site of Nsp14 diminished these inhibitory activities. Targeted capillary electrophoresis-mass spectrometry analysis (CE-MS) unveiled the production of N7-methyl-GTP in Nsp14-expressing cells. Association of the nuclear cap-binding complex (NCBC) with the mRNA cap and subsequent recruitment of U1 snRNP and the stem-loop binding protein (SLBP) were impaired by Nsp14. These data suggest that the defects in mRNA processing and export arise from the compromise of NCBC function by N7-methyl-GTP, thus exemplifying a novel viral strategy to block host gene expression.

Metronomic dosing of selinexor in select soft tissue sarcomas (STS).

11557 Background: Selinexor (S) is a first-in-class, oral, selective inhibitor of nuclear export (SINE). S has a demonstrated anti-tumor activity in STS. However, the use of S can be associated with toxicities, such as nausea, anorexia and fatigue. A modified dosing schedule may improve the tolerability of S without compromising its efficacy. Methods: We evaluated S when given metronomically in patients (pts) with advanced metastatic leiomyosarcoma, endometrial stromal sarcoma, and malignant peripheral nerve sheath tumors. S was administered daily for 4-days in a row followed by 3-days break, repeated weekly in a 28-days cycle. Dose levels (DL) were escalated using a 3+3 design to determine maximum tolerated dose. DL included 2.5mg (DL1), 5mg (DL2), 7.5mg (DL3), 10 mg (DL4), 12.5 mg (DL5), 15 mg (DL6) and 17.5 mg (DL7). S was administered until unacceptable toxicities or disease progression. Imaging was performed every 8 weeks. Primary objectives were safety and tolerability as well as the determination of the recommended phase II dose. Secondary objectives were anti-tumor activity, toxicity profile, and pharmacokinetics (PK) profile. Results: Twenty-five pts (22 females/3 males, median age 59 years [range 35-84]) were enrolled at different DL (3, 3, 4, 6, 6, 3 pts at DL1 to DL6 respectively). The most common adverse events (AE) of any grade were constipation (n = 11, 50%), nausea (n = 11, 50%), and dysgeusia (n = 10, 45%). Eight (36%) pts experienced G3/4 AE while on trial; most were hematological toxicities seen in 3 (14%) pts (anemia, neutropenia, and leukopenia, n = 1 each). Non-hematological G3/4 AE were seen in 5 (23%) pts (Including: colonic obstruction, atrial fibrillation, and spinal cord compression, n = 1 each). Two Dose limiting toxicities were experienced, at DL4 (thrombocytopenia) and DL5 (transaminitis). Twenty-two pts were evaluable for response; 10 (45%) pts had stable disease (SD) as best response. Eight pts with SD had disease stability of > 4 months. Twelve pts (55%) had progressive disease. Median progression-free survival was 2.4 months (95% CI 1.7-5.3 months). PK data is awaiting final analysis. Conclusions: Metronomic S demonstrated tolerability in selected sarcoma pts. Signs of potential clinical benefit was seen in the form of SD. Further data comparison with historical controls and PK analysis are needed to put this finding into perspective. Clinical trial information: NCT04811196 .

Racial differences in outcomes of patients with relapsed/refractory multiple myeloma treated with selinexor.

e20016 Background: Multiple Myeloma (MM) is the 2nd most common hematologic malignancy in the US, though survival in patients with MM has improved over the past decade. Survival improvements in African Americans (AAs) have been smaller, which may be due to disparity in access to therapies. There are also key differences in MM biology between races, including higher rates of IgA disease and genetics. Given underrepresentation of minorities in clinical trials, we analyzed whether outcomes were similar between AAs and other races in the phase 2 STORM trial (NCT02336815) of selinexor. Selinexor, an oral, first-in-class selective inhibitor of nuclear export via exportin 1, has proven efficacy for refractory MM. To our knowledge, this is the first race subgroup analysis of selinexor in any clinical trial. Methods: Pts from STORM who received study drug (N = 202) were included. Pts with heavily pretreated MM, including triple-class and penta- refractory MM refractory to the last line of therapy were given selinexor (80mg) + dexamethasone (20mg) twice weekly. We conducted a retrospective racial subgroup analysis. Cox proportional modeling was used to determine the hazard ratio (HR) for MM relapse between races controlling for covariates. Results: AAs represented 17% of pts (35 AAs, 148 White, 2 Asian, 11 other and 6 missing). AAs were younger compared to other races (median age 60.7 vs 65.3) with more females (74.3% vs 40.7%). Cytogenetic abnormalities and R-ISS staging were similar between races. AAs had a median progression free survival (PFS) of 6.5 mos (95% CI 4.7, NR) compared with 3.7 mos (95% CI 2.8, 4.6; p = 0.035) for other races. Overall response rate (ORR) was 25.7% (95% CI 12.5, 43.3) in AA pts vs 23.4% [17.2, 30.5] in other races), clinical benefit rate (37.1% [21.5, 55.1] vs 35.9% [28.7, 43.7]), median duration of response (5.6 mos [2.1, NR] vs 5.3 [3.6, NR]), median duration of treatment (9 wks [IQR 3-22 wks] vs 8 wks [4-16 wks]), and mean dose intensity (117.9 mg/wks [STD 35.1] vs 117.1 [34.7]) were similar between grps. Rates of Adverse Events (AEs) ≥ grade 3 (94.3% vs 95.8%), and AE-related dose reductions (45.7% vs 54.5%), discontinuations (22.9% vs 30.5%), and deaths (5.7% vs 10.8%) were also similar. The adjusted HR for MM relapse in AAs was 0.45 (95% CI 0.22, 0.92; p = 0.028) after controlling for gender, age and prior therapy. Conclusions: This subgroup analysis showed that compared with other races, AAs pts were younger and included a greater percentage of women. Although ORRs were similar, AAs had a longer PFS compared with other races after adjusting for covariates. Despite small sample size, the differences were statistically significant. It is unclear if the better PFS reflects a different biology, pharmacology of selinexor or both. Dose adjustments and tolerability were relatively comparable. These results could assist in the placement of selinexor in the treatment sequence of relapsed refractory MM for AAs.

Nuclear Export Inhibitor Selinexor Enhances Oncolytic Myxoma Virus Therapy against Cancer.

We demonstrated that a combination of nuclear export inhibitor selinexor and oncolytic MYXV significantly enhanced viral replication, reduced cancer cell proliferation, reduced tumor burden, and enhanced the overall survival of animals. Thus, selinexor and oncolytic MYXV can be used as potential new anticancer therapy.

Selinexor and Other Selective Inhibitors of Nuclear Export (SINEs)—A Novel Approach to Target Hematologic Malignancies and Solid Tumors

Exportin 1 (XPO1) is a crucial molecule of nucleocytoplasmic transport. Among others, it exports molecules important for oncogenesis from the nucleus to the cytoplasm. The expression of XPO1 is increased in numerous malignancies, which contributes to the abnormal localization of tumor suppressor proteins in the cytoplasm and subsequent cell cycle dysregulation. Selective inhibitors of nuclear export (SINEs) are novel anticancer agents that target XPO1, arrest tumor suppressor proteins in the nucleus, and induce apoptosis in cancer cells. Selinexor, a first-in-class SINE, has already been approved for the treatment of relapsed/refractory multiple myeloma and relapsed/refractory diffuse large B cell lymphoma not otherwise specified. It has also been proven effective in relapsed/refractory and previously untreated acute myeloid leukemia patients. In addition, numerous studies have yielded promising results in other malignancies of the hematopoietic system and solid tumors. However, future clinical use of selinexor and other SINEs may be hampered by their significant toxicity.

Recent advance of small-molecule drugs for clinical treatment of multiple myeloma

Multiple myeloma (MM) is a hematologic neoplasm of plasma cells that is currently deemed incurable. Despite the introduction of novel immunomodulators and proteasome inhibitors, MM remains a challenging disease with high rates of relapse and refractoriness. The management of refractory and relapsed MM patients remains a formidable task, primarily due to the emergence of multiple drug resistance. Consequently, there is an urgent need for novel therapeutic agents to address this clinical challenge. In recent years, a significant amount of research has been dedicated to the discovery of novel therapeutic agents for the treatment of MM. The clinical utilization of proteasome inhibitor carfilzomib and immunomodulator pomalidomide has been successively introduced. As basic research continues to advance, novel therapeutic agents, including panobinostat, a histone deacetylase inhibitor, and selinexor, a nuclear export inhibitor, have progressed to the clinical trial and application phase. This review aims to furnish a comprehensive survey of the clinical applications and synthetic pathways of select drugs, with the intention of imparting valuable insights for future drug research and development geared towards MM.

Selective nuclear export inhibitor KPT‑330 enhances the radiosensitivity of esophageal carcinoma cells.

Although the concurrent application of definitive chemoradiation has improved the prognosis of patients with esophageal cancer, resistance to therapy poses a major threat to treatment. The present study aimed to investigate whether the use of KPT-330, a selective inhibitor of nuclear export (SINE), enhances the radiosensitivity of esophageal cancer cells. Immunohistochemical staining assays were employed to evaluate the expression and prognostic significance of chromosome maintenance protein-1 (CRM1) in 111 esophageal carcinoma (ESCA) tissues collected from patients with esophageal squamous cell carcinoma. The data showed that the expression of CRM1 in the ESCA tissues was significantly upregulated compared with that in the normal adjacent tissues. Furthermore, patients with higher CRM1 expression had significantly decreased overall survival compared with those with lower CRM1 expression. The effects of KPT-330 and/or radiation on ECA109 human ESCA cells were also evaluated. KPT-330 suppressed the viability of the ECA109 cells. A colony formation assay demonstrated that a combination of KPT-330 and radiation significantly decreased ECA109 cell proliferation. Flow cytometric analysis showed that KPT-330 increased the arrest of the ECA109 cells at the G2/M phase and induced apoptosis. In addition, western blotting revealed that the inhibitory effect of KPT-330 on cell viability was associated with the increased expression of p53 and promotion of the nuclear accumulation of the p53 protein. In conclusion, the present study demonstrated that CRM1 expression is associated with the prognosis of patients with ESCA following radiotherapy. The inhibition of CRM1 expression by the SINE inhibitor KPT-330 increases radiosensitivity and is potentially useful in a combination treatment strategy for esophageal cancers.

APEX3 – An Optimized Tool for Rapid and Unbiased Proximity Labeling

Macromolecular interactions regulate all aspects of biology. The identification of interacting partners and complexes is important for understanding cellular processes, host-pathogen conflicts, and organismal development. Multiple methods exist to label and enrich interacting proteins in living cells. Notably, the soybean ascorbate peroxidase, APEX2, rapidly biotinylates adjacent biomolecules in the presence of biotin-phenol and hydrogen peroxide. However, during initial experiments with this system, we found that APEX2 exhibits a cytoplasmic-biased localization and is sensitive to the nuclear export inhibitor leptomycin B (LMB). This led us to identify a putative nuclear export signal (NES) at the carboxy-terminus of APEX2 (NESAPEX2), structurally adjacent to the conserved heme binding site. This putative NES is functional as evidenced by cytoplasmic localization and LMB sensitivity of a mCherry-NESAPEX2 chimeric construct. Single amino acid substitutions of multiple hydrophobic residues within NESAPEX2 eliminate cytoplasm-biased localization of both mCherry-NESAPEX2 as well as full-length APEX2. However, all but one of these NES substitutions also compromises peroxide-dependent labeling. This unique separation-of-function mutant, APEX2-L242A, is termed APEX3. Localization and functionality of APEX3 are confirmed by fusion to the nucleocytoplasmic shuttling transcriptional factor, RELA. APEX3 is therefore an optimized tool for unbiased proximity labeling of cellular proteins and interacting factors..