XPO1 Inhibitor Research Articles

Capitalizing on the absence of TP53 mutations in low-grade serous and clear cell ovarian cancer with XPO1 inhibition

Capitalizing on the absence of TP53 mutations in low-grade serous and clear cell ovarian cancer with XPO1 inhibition

NPM1-fusion proteins promote myeloid leukemogenesis through XPO1-dependent HOX activation.

Nucleophosmin (NPM1) is a nucleolar protein and one of the most frequently mutated genes in acute myeloid leukemia (AML). In addition to the commonly detected frameshift mutations in exon12 (NPM1c), previous studies have identified NPM1 gene rearrangements leading to the expression of NPM1-fusion proteins in pediatric AML. However, whether the NPM1-fusions are indeed oncogenic and how the NPM1-fusions cause AML have been largely unknown. In this study, we investigated the subcellular localization and leukemogenic potential of two rare NPM1-fusion proteins, NPM1::MLF1 and NPM1::CCDC28A. NPM1::MLF1 is present in both the nucleus and cytoplasm and occasionally induces AML in the mouse transplantation assay. NPM1::CCDC28A is more localized to the cytoplasm, immortalizes mouse bone marrow cells in vitro and efficiently induces AML in vivo. Mechanistically, both NPM1-fusions bind to the HOX gene cluster and, like NPM1c, cause aberrant upregulation of HOX genes in cooperation with XPO1. The XPO1 inhibitor selinexor suppressed HOX activation and colony formation driven by the NPM1-fusions. NPM1::CCDC28A cells were also sensitive to menin inhibition. Thus, our study provides experimental evidence that both NPM1::MLF1 and NPM1::CCDC28A are oncogenes with functions similar to NPM1c. Inhibition of XPO1 and menin may be a promising strategy for the NPM1-rearranged AML.

Allosteric degraders induce CRL5 ASB8 mediated degradation of XPO1.

The nuclear export receptor Exportin 1 (XPO1/CRM1) is often overexpressed in cancer cells resulting in aberrant localization of many cancer-related protein cargoes. The XPO1 inhibitor and cancer drug selinexor (KPT-330), and its analog KPT-185, block XPO1-cargo binding thereby restoring cargo localization. Selinexor binding induces cullin-RING E3 ubiquitin ligase (CRL) substrate receptor ASB8-mediated XPO1 degradation. Here we reveal the mechanism of inhibitor-XPO1 engagement by CRL5ASB8. Cryogenic electron microscopy (cryo-EM) structures show ASB8 binding to a large surface of selinexor/KPT-185-XPO1 that includes a three-dimensional degron unique to the drug-bound exportin. The structure explains weak XPO1-ASB8 binding in the absence of selinexor/KPT-185 that is unproductive for proteasomal degradation, and the substantial affinity increase upon selinexor/KPT-185 conjugation, which results in CRL5 ASB8 -mediated XPO1 ubiquitination. In contrast to previously characterized small molecule degraders, which all act as molecular glues, selinexor/KPT-185 binds extensively to XPO1 but hardly contacts ASB8. Instead, selinexor/KPT-185 binds XPO1 and stabilizes a unique conformation of the NES/inhibitor-binding groove that binds ASB8. Selinexor/KPT-185 is an allosteric degrader. We have explained how drug-induced protein degradation is mediated by a CRL5 system through an allosteric rather than a molecular glue mechanism, expanding the modes of targeted protein degradation beyond the well-known molecular glues of CRL4.

HMGB2-induced calreticulin translocation required for immunogenic cell death and ferroptosis of cancer cells are controlled by the nuclear exporter XPO1

Cisplatin and oxaliplatin cause the secretion of high mobility group box 1 (HMGB1) protein from cancer cells, which is necessary for initiation of immunogenic cell death (ICD). Calreticulin (CRT) translocation from the endoplasmic reticulum to the plasma membrane is also required; oxaliplatin induces this translocation but cisplatin does not. We have discovered that oxaliplatin causes the secretion of both HMGB1 and HMGB2 from the cell nucleus into the extracellular milieu. We previously showed that cisplatin-mediated secretion of HMGB1 is controlled by the nuclear exporter XPO1 (chromosomal maintenance 1; CRM1). We now find that XPO1 regulates oxaliplatin-mediated secretion of both HMGB1 and HMGB2. XPO1 inhibition causes nuclear accumulation of both proteins, inhibition of oxaliplatin-mediated ferroptosis of colon cancer cells, and inhibition of CRT translocation to the plasma membrane of lung and colon cancer cells. Incubation of cancer cells with cell targeted (CT)-HMGB2 confirmed that HMGB2 is required for the CRT translocation. Furthermore, CT-HMGB2 is three orders of magnitude more potent at inducing CRT translocation than oxaliplatin.

Recent advances in AML with mutated NPM1.

Nucleophosmin 1 (NPM1) mutation is one of the most prevalent genetic mutations in adult acute myeloid leukemia (AML) and is particularly predominant in AML with a normal karyotype. NPM1 is a chaperone protein that plays various roles in several cellular processes. Wild-type NPM1 is normally localized to the nucleus, whereas mutant NPM1 proteins exhibit altered cytoplasmic localization. Clinically, AML with mutated NPM1 without FLT3-ITD is associated with a higher complete remission rate and improved overall survival. AML with mutated NPM1 is categorized as a distinct genetic entity in the World Health Organization classification of hematopoietic malignancies due to its unique clinical and biological features. However, the precise roles of NPM1 in normal hematopoiesis and in AML development remain unclear. Recent studies have revealed various clinical applications of NPM1 mutations in AML treatment, particularly in measurable residual disease analyses that target mutant NPM1 transcripts and in potential therapeutic applications of menin inhibitors and XPO-1 inhibitors for AML with mutated NPM1. Thus, NPM1 mutation is highly significant in AML classification, prognosis, response assessment, and molecular targeted therapies. Here, we review recent progress in clinical and biological aspects of AML with mutated NPM1 including molecular targeted therapy.

Application and Research Progress of Selinexor in Hematologic Tumors Other Than Multiple Myeloma --Review

Exportin-1 (XPO1) is a major transporter for hundreds of proteins. Selinexor is the first generation XPO1 inhibitor. At present, selinexor has gained more attention in the application of multiple myeloma (MM). Meanwhile, the latest clinical trials have confirmed that whether it is a single agent or combined with other chemotherapy regimens, selinexor can also achieve good therapeutic effects in patients with leukemia and lymphoma. This review summarizes the results of preclinical studies and clinical trials of selinexor in treatment of non-MM hematological malignancies, aiming to explore how to choose single agent or in combination with other regimens as induction chemotherapy.

Altered RNA export by SF3B1 mutants confers sensitivity to nuclear export inhibition

SF3B1 mutations frequently occur in cancer yet lack targeted therapies. Clinical trials of XPO1 inhibitors, selinexor and eltanexor, in high-risk myelodysplastic neoplasms (MDS) revealed responders were enriched with SF3B1 mutations. Given that XPO1 (Exportin-1) is a nuclear exporter responsible for the export of proteins and multiple RNA species, this led to the hypothesis that SF3B1-mutant cells are sensitive to XPO1 inhibition, potentially due to altered splicing. Subsequent RNA sequencing after XPO1 inhibition in SF3B1 wildtype and mutant cells showed increased nuclear retention of RNA transcripts and increased alternative splicing in the SF3B1 mutant cells particularly of genes that impact apoptotic pathways. To identify novel drug combinations that synergize with XPO1 inhibition, a forward genetic screen was performed with eltanexor treatment implicating anti-apoptotic targets BCL2 and BCLXL, which were validated by functional testing in vitro and in vivo. These targets were tested in vivo using Sf3b1K700E conditional knock-in mice, which showed that the combination of eltanexor and venetoclax (BCL2 inhibitor) had a preferential sensitivity for SF3B1 mutant cells without excessive toxicity. In this study, we unveil the mechanisms underlying sensitization to XPO1 inhibition in SF3B1-mutant MDS and preclinically rationalize the combination of eltanexor and venetoclax for high-risk MDS.

CDK4/6 inhibition augments anti-tumor efficacy of XPO1 inhibitor selinexor in natural killer/T-cell lymphoma

XPO1 is an attractive and promising therapeutic target frequently overexpressed in multiple hematological malignancies. The clinical use of XPO1 inhibitors in natural killer/T-cell lymphoma (NKTL) is not well documented. Here, we demonstrated that XPO1 overexpression is an indicator of poor prognosis in patients with NKTL. The compassionate use of the XPO1 inhibitor selinexor in combination with chemotherapy showed favorable clinical outcomes in three refractory/relapsed (R/R) NKTL patients. Selinexor induced complete tumor regression and prolonged survival in sensitive xenografts but not in resistant xenografts. Transcriptomic profiling analysis indicated that sensitivity to selinexor was correlated with deregulation of the cell cycle machinery, as selinexor significantly suppressed the expression of cell cycle-related genes. CDK4/6 inhibitors were identified as sensitizers that reversed selinexor resistance. Mechanistically, targeting CDK4/6 could enhance the anti-tumor efficacy of selinexor via the suppression of CDK4/6-pRb-E2F-c-Myc pathway in resistant cells, while selinexor alone could dramatically block this pathway in sensitive cells. Overall, our study provids a preclinical proof-of-concept for the use of selinexor alone or in combination with CDK4/6 inhibitors as a novel therapeutic strategy for patients with R/R NKTL.

Exportin 1 governs the immunosuppressive functions of myeloid-derived suppressor cells in tumors through ERK1/2 nuclear export.

Myeloid-derived suppressor cells (MDSCs) are a main driver of immunosuppression in tumors. Understanding the mechanisms that determine the development and immunosuppressive function of these cells could provide new therapeutic targets to improve antitumor immunity. Here, using preclinical murine models, we discovered that exportin 1 (XPO1) expression is upregulated in tumor MDSCs and that this upregulation is induced by IL-6-induced STAT3 activation during MDSC differentiation. XPO1 blockade transforms MDSCs into T-cell-activating neutrophil-like cells, enhancing the antitumor immune response and restraining tumor growth. Mechanistically, XPO1 inhibition leads to the nuclear entrapment of ERK1/2, resulting in the prevention of ERK1/2 phosphorylation following the IL-6-mediated activation of the MAPK signaling pathway. Similarly, XPO1 blockade in human MDSCs induces the formation of neutrophil-like cells with immunostimulatory functions. Therefore, our findings revealed a critical role for XPO1 in MDSC differentiation and suppressive functions; exploiting these new discoveries revealed new targets for reprogramming immunosuppressive MDSCs to improve cancer therapeutic responses.

MODL-15. CHARACTERIZATION OF SPONTANEOUS CANINE HIGH-GRADE GLIOMA MODELS AS CLINICALLY-RELEVANT SURROGATES OF PEDIATRIC HIGH-GRADE GLIOMA

Abstract BACKGROUND High-grade glioma (HGG) occurring spontaneously in canines shows histological and genetic resemblance to pediatric high-grade glioma (PHGG). Both canine HGG and PHGG are treated with combinations of surgical resection, radiation therapy, and/or chemotherapy, but outcomes for both groups are poor. Studying canine HGG both serves companion dogs and provides an orthogonal preclinical model of PHGG. METHODS Canine HGG lines J3T, SDT3G, and G06A were characterized and compared with H3K27M-mutant PHGG lines DIPG7, DIPG13, and BT245 using neurosphere dilution assay and drug screening with all FDA-approved anti-cancer agents. J3T and SDT3G were orthotopically implanted into mice and monitored using MRI and bioluminescence. RESULTS Like PHGG, the canine lines J3T and SDT3G were highly sensitive to proteasome and XPO1 inhibition; compared to PHGG, the canine lines were most sensitive to protein translation inhibitors and DNA intercalators. Canine HGG lines were not as sensitive to other targeted inhibitors effective in PHGG. Compared to PHGG cell lines, canine cell lines had greater variance in self-renewal capability. J3T and SDT3G were also injected into the cortex of immunodeficient mice. Bioluminescent signal confirmed J3T engraftment one week post-surgery with rapid tumor growth, while SDT3G presented initial engraftment by MRI two weeks post-surgery but did not exhibit sustained growth. DISCUSSION Canine HGG and PHGG showed similar sensitivity to proteasome and XPO1 inhibition; they differed in self-renewal capability and susceptibility to other anti-cancer agents. This could be because canine target proteins often differ from their human counterparts and thus may respond differently to targeted medications designed for humans. Overall, canine HGG provides a novel, primary, immunocompetent surrogate that resembles PHGG and may provide a step for clinical investigation between xenograft models and PHGG trials and/or opportunities for co-clinical trials.

ETMR-18. ADVANCING ETMR RESEARCH: NOVELIN VITRO ANDIN VIVO PRECLINICAL MODELS FOR DEVELOPING MORE EFFECTIVE TREATMENTS

Abstract BACKGROUND Embryonal Tumor with Multilayered Rosettes (ETMR) is a rare and aggressive tumor that occurs mainly in infants under three years of age. Genetically, ETMRs are characterized by amplification and fusion of a microRNA cluster on chromosome 19 (C19MC) with TTYH1, present in ~90% of the tumors. ETMR patients still have a poor prognosis without any recent advances in treatment. A major limitation to develop more effective treatment strategies is the lack of sufficient preclinical models. METHODS Establishment of ETMR patient-derived xenograft (PDX) models and tumoroid lines, molecular characterization, high throughput in vitro drug screens, targeted drug treatments in vitro and in vivo. RESULTS We have established four new tumoroid and five new PDX ETMR models. These models faithfully recapitulate ETMR patients’ tumors based on their histological, transcriptomic, and methylome signatures. The in vitro models were derived from two patients and two PDX models and included three C19MC-amplified cell lines, of which two were a primary-relapse pair, and one a primary C19MC non-amplified model. In vivo we established the same models as PDX models subcutaneously plus an additional C19MC-amplified relapse model. High-throughput drug screening assays, using drug libraries with 225 clinically approved drugs and other small molecules, were conducted across the panel of in vitro models. Potential therapeutic candidates with promising activity in ETMR tumoroid lines identified from these screens include FGFR, XPO1, MTOR, MDM2 and topoisomerase inhibitors. CONCLUSIONS The establishment of novel preclinical models represents a significant advancement in ETMR research, offering a platform that captures the molecular complexity of the disease. The identification of several inhibitors shows the potential of these models for drug discovery and preclinical testing. Ongoing in vitro and in vivo experiments with these drugs and combinations aim to further validate their activity, moving towards the development of more effective therapies for ETMR patients.

EPEN-04. OVERWHELMING ZFTA-RELA NUCLEAR LOCALIZATION AS A THERAPEUTIC STRATEGY AGAINST EPENDYMOMA

Abstract BACKGROUND Pediatric ependymoma is a malignant brain tumor without targeted therapies. The 10-year survival is close to 50%, as this relentless tumor often relapses years following initial diagnosis. Over two thirds of supratentorial ependymomas harbor a gene fusion between ZFTA and RELA (ZFTA-RELA). Despite evidence that ZFTA-RELA drives tumorigenicity, mechanistic details remain elusive, hindering efforts to uncover therapeutic vulnerabilities. Since direct targeting of ZFTA-RELA is not currently possible, we hypothesized that ZFTA-RELA fusion binding partners would represent vulnerabilities amenable to therapeutic targeting. METHODS We investigated the biochemical basis of ZFTA-RELA, with the goal of identifying key members of the protein interaction landscape. This was performed in our in utero electroporation mouse model of ZFTA-RELA ependymoma. A series of sucrose gradient and immuno-precipitation experiments were performed, coupled with mass spectrometry. ZFTA-RELA interaction proteins were functionalized using focused CRIPSR-Cas9 library screens in cell cultures. Critically, these revealed novel dependencies and druggable targets, with XPO1 emerging as a lead candidate. In vitro and in vivo studies were conducted to evaluate targeting XPO1 in ZFTA-RELA ependymoma. RESULTS ZFTA-RELA regulates XPO1 gene transcription, and elevated gene expression is associated with poor survival in these patients. While expression of ZFTA-RELA is necessary for oncogenic transcription, extremely elevated nuclear localization is associated with reduced growth. This suggests a ‘goldilocks’ model in which XPO1 titrates precise levels of nuclear ZFTA-RELA protein. We reveal that a potential therapeutic vulnerability emerges through modulation of ZFTA-RELA nuclear localization. Supporting this, chemical inhibition of XPO1 using Selinexor, has a direct effect on ZFTA-RELA cellular localization patterns. Critically, in patient derived orthotopic xenograft models, XPO1 inhibition exerts anti-tumor effects both in vitro and in vivo. CONCLUSION Our findings reveal a novel therapeutic strategy in ependymoma, and provide the mechanistic and pre-clinical data needed to develop a clinical trial for patients with ZFTA-RELA ependymoma.

Phase 3 randomized double-blind study evaluating selinexor, an XPO1 inhibitor, plus ruxolitinib in JAKi-naïve myelofibrosis.

TPS6594 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm with common somatic gene driver mutations in JAK2, CALR, and MPL. Selinexor, an investigational oral XPO1 inhibitor, may inhibit MF-relevant JAK/STAT and non-JAK/STAT pathways. Preclinical studies have shown potential synergy with ruxolitinib treatment. In the phase 1 portion of XPORT-MF-034 evaluating selinexor plus ruxolitinib in JAKi-naïve patients with MF, the most common AEs in the 60 mg cohort were nausea (79%), anemia (64%), thrombocytopenia (64%), and fatigue (57%). Nausea was predominantly Grade 1 and transient in nature. Treatment-related AEs leading to treatment discontinuation were thrombocytopenia (n=1) and neuropathy (n=1). SVR35 and TSS50 was achieved by 79% and 58% of the 60 mg cohort intent-to-treat population at Week 24, respectively. Response rates were consistent across subgroups, including sex and regardless of ruxolitinib starting dose. These data provide strong support to further evaluate selinexor (60 mg) and ruxolitinib in patients with JAKi-naïve MF. Methods: The XPORT-MF-034 (NCT04562389) trial includes a global, Phase 3 randomized, double-blind, placebo-controlled study designed to evaluate selinexor and ruxolitinib. JAKi-naïve patients with MF will be randomized 2:1 to receive oral selinexor 60 mg or placebo once weekly (28-day cycle) and twice daily ruxolitinib. Randomization will be stratified by DIPSS risk category (int-1 vs int-2 or high-risk), spleen volume (<1800 cm3 vs >1800 cm3 by MRI/CT scan), and baseline platelet counts (100-200x109/L vs >200x109/L). Dual anti-emetics for nausea prophylaxis will be required for the first two cycles. Select eligibility criteria include ≥18 years of age, spleen volume ≥450 cm3 by MRI or CT, DIPSS intermediate-1, intermediate-2, or high-risk, active symptoms of MF (MFSAF v4.0), currently not eligible for stem cell transplantation, ECOG≤2, and platelet count ≥100 x 109/L. Select exclusion criteria include >10% blasts in peripheral blood or bone marrow; previous treatment with JAKi for MF, or previous treatment with selinexor or other XPO1 inhibitors. The co-primary study endpoints are SVR35 and TSS50 at Week 24 and will be tested hierarchically. The key secondary endpoint is anemia response at Week 24 per the IWG-MRT and ELN criteria. The XPORT-MF-034 Phase 3 trial is currently open for enrollment; a total of 306 JAKi-naïve MF patients will be enrolled and the study was initiated on June 28, 2023. Clinical trial information: NCT04562389 .

Selinexor combined with tislelizumab in patients with relapsed or refractory extranodal NK/T-cell lymphoma (R/R ENKTL): Results of dose escalation of cohort C, from a multicenter, single-arm, phase I/II study (TOUCH).

7065 Background: ENKTL is a rare subtype of mature T and NK/T cell lymphoma presenting features of highly aggressive clinical course and association with EBV infection.The prognosis remains poor for R/R ENKTL patients (pts) with treatment failure of L-Aspariginase (L-Asp) based regimens, highlighting the need for novel approaches. Monotherapy of tislelizumab (Tis) showed preliminary clinical activity in R/R ENKTL. Selinexor (Sel), a novel XPO1 inhibitor, has demonstrated preclinical synergistic effects when combined with PD-1 antibody. The TOUCH study (NCT04425070) includes three cohorts investigating the combination of Sel with chemotherapy (ICE or GEMOX) or Tis in R/R ENKTL. Methods: Cohort C was designed to evaluate the safety, tolerability, preliminary efficacy of Sel plus Tis in R/R ENKTL. Pts who received at least one prior treatment containing L-Asp were enrolled. In the escalation stage, a 3+3 design was implemented to determine the RP2D of Sel. The starting dose of Sel was 40 mg QW, followed by 60 mg QW (dose level 2), administered orally on Days 1, 8, and 15 of each 21-day cycle. Tis was administered at a fixed dose of 200 mg every 3 weeks on Day 1. DLTs were assessed during the first cycle. Efficacy was evaluated per Lyric 2016. Results: As of 25 Dec 2023, 12 R/R ENKTL pts were enrolled in the escalation stage [Sel 40mg (n=3); Sel 60mg (n=9)]. At study entry, the median age was 52 years (range 32-65); Five males and 7 females; 6 (50.0%) had stage III/IV disease; Seven (58.3%) pts had PINK score ≥2 and 6 (50.0%) pts were circular EBV-DNA positive. The median number of prior treatment lines was 2.5 (range 1-5); Ten (83.3%) pts were refractory to their last-line therapy. Eleven pts had prior exposure to PD-1/PD-L1 antibodies, including 7 pts who had received prior Tis. No DLT was observed and MTD was not reached. The most common TEAEs were asthenia (83.3%), neutropenia (83.3%), nausea/vomiting (58.3%), decreased appetite, weight loss, anemia, thrombocytopenia (50.0%, respectively), lymphocytopenia (41.7%), pneumonia, AST increased and proteinuria (33.3%, respectively). Only 1 pt experienced an irAE with thyroiditis. Seven pts (58.3%) had Grade≥3 TEAEs. TESAEs occurred in 3 pts (25%) with only 1 (sepsis) considered treatment related. No pt discontinued or died due to TEAEs. Among 11 efficacy evaluable patients, ORR was 72.7% (8/11), and CR rate was 36.4% (4/11). Of 7 Tis exposed pts, 2 achieved CR and 3 achieved PR. At a median follow-up of 6.8 months (range 5.5-12.6), the median PFS, DOR and OS were 6.1 months, 4.7 months, and not reached (6-month OS rate 90.9%), respectively. The RP2D of Sel in Cohort C was determined to be 60mg QW. Conclusions: Selinexor plus tislelizumab showed tolerable safety profile and encouraging response rate in R/R ENKTL. Expansion stage of Cohort C is ongoing. Clinical trial information: NCT04425070 .

Phase 2 study evaluating selinexor monotherapy in patients with JAKi-naïve myelofibrosis and moderate thrombocytopenia.

TPS6593 Background: While multiple JAKi therapies are approved in myelofibrosis, thrombocytopenia, which commonly occurs in myelofibrosis and is associated with poor outcomes, is an on-target side effect; use of suboptimal ruxolitinib doses used to manage adverse effects leads to reduced efficacy. In a Phase 1 study (NCT04562389) of selinexor, an investigational XPO1 inhibitor, plus the JAKi ruxolitinib in JAKi-naïve myelofibrosis the most common AEs in the 60 mg cohort were nausea (79%), anemia (64%), thrombocytopenia (64%), and fatigue (57%). Nausea events were predominantly Grade 1 and transient in nature. Among patients who received at least one prophylactic antiemetic (64% of 60 mg cohort), nausea (Grade 1 only) was experienced by 67% of patients compared with 100% of those who did not receive prophylactic antiemetics (Grades 1-3). In the selinexor 60 mg cohort, 79% of the intent-to-treat population achieved SVR35 and 58% achieved TSS50 at Week 24. Response rates were consistent across subgroups, including sex and regardless of ruxolitinib dose. In a Phase 2 study, selinexor monotherapy in patients with myelofibrosis refractory or intolerant to JAKi therapy (NCT03627403; ESSENTIAL) was generally tolerable and preliminary signs of efficacy were observed with single-agent selinexor. These results provide rationale to explore selinexor monotherapy in myelofibrosis subpopulations with high unmet need such as those with thrombocytopenia. Methods: XPORT-MF-044 (NCT05980806) is a two arm, sequential, multicenter, open-label, Phase 2 study evaluating the efficacy of selinexor (40 mg or 60 mg QW; N=29 per arm) in patients with JAKi-naïve MF and moderate thrombocytopenia (platelet count: 50-100x109/L) with optional expansion arms (n=30 per arm). Optional ruxolitinib or pacritinib, or momelotinib treatment (based on platelet count) may be added for patients whose SVR from baseline is <10% at week 12 or <35% at week 24. Inclusion criteria include ≥18 years of age, spleen volume ≥450 cm3 by MRI or CT scan, DIPSS intermediate-1 with symptoms, intermediate-2, or high-risk, ECOG ≤2, platelet counts of 50-100x109 /L, and not eligible for stem cell transplantation. Select exclusion criteria include >10% blast in peripheral blood or bone marrow and previous treatment with JAKi for myelofibrosis. Primary endpoint is SVR35 at week 24. Key secondary endpoints are safety, TSS50 at week 24, anemia response at week 24, overall survival, and overall response rate. Clinical trial information: NCT05980806 .

Phase 1/2 trial of the XPO1 inhibitor selinexor in combination with docetaxel in previously treated, advanced KRAS mutant non-small cell lung cancer (NSCLC).

8597 Background: KRAS mutant NSCLC remains a therapeutic challenge. Although KRAS G12C inhibitors are now approved for cases harboring that specific mutation, their efficacy is modest and the G12C variant accounts for only 40% of KRAS mutations in NSCLC. To date, there are no approved targeted therapies for non-G12C KRAS mutant NSCLC. Selective inhibitors of nuclear export (SINE) modulate cancer cell biology by retaining certain proteins—such as tumor suppressors—within the nucleus, where they remain physiologically active. The XPO1 inhibitor selinexor demonstrated efficacyinpreclinicalNSCLC models harboring various KRAS mutations. Methods: In this 3 + 3 dose-escalation phase 1/2 trial, patients with previously treated advanced KRAS mutant NSCLC received selinexor (dosed orally weekly) plus docetaxel 75 mg/m2 IV every three weeks (NCT03095612). Prior treatment with KRAS G12C inhibitors was permitted. Results: Among 40 enrolled patients, median age was 66 years, 22 (55%) were female, and 34 (85%) were white. KRAS mutation types included G12C (28%), G12V (23%), G12D (20%), G12A (13%), G12R (5%), G13C (5%), and one case each of G12S, G13D, Q61L, and K117N. Patients had received a median of 2 prior lines of therapy (range 1-4). The maximum tolerated dose of selinexor was 60 mg PO weekly combined with docetaxel. The most common adverse events (AE) were nausea (73%, Gr ≥3 8%), fatigue (70%, Gr ≥3 5%), neutropenia (65%, Gr ≥3 60%), diarrhea (58%, Gr ≥3 10%), anorexia (50%, Gr ≥3 0%), and vomiting (45%, Gr ≥3 5%). Of 32 patients evaluable for efficacy, 7 (22%) had partial response (PR) and 18 (56%) had stable disease (SD) as best response. Median progression-free survival (PFS) was 4.1 months (95% CI, 2.9-5 months); median overall survival (OS) was 7.1 months (95% CI, 4.5-13.7 months). Clinical outcomes did not differ significantly among KRAS mutation types. However, TP53co-mutations (48%) were associated with significantly worse outcomes: disease control rate (PR + SD) 27% vs 92% ( P=0.006); median PFS 1.8 vs 7.4 months ( P<0.001); median OS 5.8 vs 17 months ( P=0.006). Additional biomarker studies are ongoing. Conclusions: Selinexor plus docetaxel is tolerated with multi-agent supportive care. The combination shows moderate efficacy across KRAS mutation types, with promising activity in TP53 wild type cases. Clinical trial information: NCT03095612 .

Adverse events reporting of XPO1 inhibitor - selinexor: a real-word analysis from FAERS database

As the world's first oral nuclear export inhibitor, selinexor is increasingly being used in clinical applications for malignant tumors. However, there is no extensive exploration on selinexor's adverse events (ADEs), necessitating a real-word assessment of its clinical medication safety. FAERS data (July 2019–June 2023) were searched for selinexor ADE reports across all indications. Use the system organ class (SOC) and preferred terms (PT) from the medical dictionary for regulatory activities (MedDRA) to describe, categorize, and statistic ADEs. Disproportionality analysis was employed through calculation of reporting odds ratio (ROR) and proportional reporting ratio (PRR). Based on total of 4392 selinexor related ADE reports as the primary suspect (PS), of which 2595 instances were severe outcomes. The predominant ADEs included gastrointestinal disorders, myelosuppression symptoms, and various nonspecific manifestations. 124 signals associated with selinexor ADE were detected, and 10 of these top 15 signals were not included into the instructions. Our study provides real-world evidence regarding the drug safety of selinexor, which is crucial for clinicians to safeguard patients’ health.

Abstract PO3-18-07: Therapeutic Potential of Combining Eltanexor with Tamoxifen to Treat Primary and Metastatic Estrogen Receptor Positive (ER+) Breast Cancers

Abstract Estrogen receptors are key pathway initiators in the aggressive development of more than two-thirds of all breast cancers. Tamoxifen (TAM) is a selective estrogen receptor modulator that disables the ER pathway and inhibits the progression of ER+ breast cancer. Unfortunately, 10-40% of patients with ER+ breast cancer who were treated with TAM experience recurrence and metastasis within 10 years. We have previously identified exportin 1 (XPO1) to be more highly expressed in breast cancers with acquired TAM resistance compared to TAM-sensitive counterparts and showed that a combination treatment of TAM with an XPO1 inhibitor, selinexor, is an effective method of tumor suppression in preclinical models. In this study we investigated the activity of eltanexor, an investigational second generation XPO1 inhibitor with minimal penetration of the blood-brain barrier, to inhibit cancer growth without leading to weight loss. Our results show that mice harboring MCF7-ESR1Y537Sxenograft tumors had significantly less (P < .05) flank tumor growth when administered a treatment regimen of TAM and eltanexor compared to control mice. In metastatic tumor models, we observed decreased metastatic burden in mice harboring MCF7-ESR1 D538G and MCF7-ESR1Y537S tumors when co-administered TAM and eltanexor. We did not observe weight changes in either model. Our findings suggest that eltanexor may be a relevant treatment for further exploration in the context of a TAM combination therapy for treatment of ER+ breast cancer. Citation Format: Vedant Jain, Myra Kamdar, Hannah McGee, Qianying Zuo, Jin Young Yoo, Yosef Landesman, Christopher Walker, Zeynep Madak-Erdogan. Therapeutic Potential of Combining Eltanexor with Tamoxifen to Treat Primary and Metastatic Estrogen Receptor Positive (ER+) Breast Cancers [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO3-18-07.

The nuclear export protein exportin-1 in solid malignant tumours: From biology to clinical trials.

Exportin-1 (XPO1), a crucial protein regulating nuclear-cytoplasmic transport, is frequently overexpressed in various cancers, driving tumor progression and drug resistance. This makes XPO1 an attractive therapeutic target. Over the past few decades, the number of available nuclear export-selective inhibitors has been increasing. Only KPT-330 (selinexor) has been successfully used for treating haematological malignancies, and KPT-8602 (eltanexor) has been used for treating haematologic tumours in clinical trials. However, the use of nuclear export-selective inhibitors for the inhibition of XPO1 expression has yet to be thoroughly investigated in clinical studies and therapeutic outcomes for solid tumours. We collected numerous literatures to explain the efficacy of XPO1 Inhibitors in preclinical and clinical studies of a wide range of solid tumours. In this review, we focus on the nuclear export function of XPO1 and results from clinical trials of its inhibitors in solid malignant tumours. We summarized the mechanism of action and therapeutic potential of XPO1 inhibitors, as well as adverse effects and response biomarkers. XPO1 inhibition has emerged as a promising therapeutic strategy in the fight against cancer, offering a novel approach to targeting tumorigenic processes and overcoming drug resistance. SINE compounds have demonstrated efficacy in a wide range of solid tumours, and ongoing research is focused on optimizing their use, identifying response biomarkers, and developing effective combination therapies. Exportin-1 (XPO1) plays a critical role in mediating nucleocytoplasmic transport and cell cycle. XPO1 dysfunction promotes tumourigenesis and drug resistance within solid tumours. The therapeutic potential and ongoing researches on XPO1 inhibitors in the treatment of solid tumours. Additional researches are essential to address safety concerns and identify biomarkers for predicting patient response to XPO1 inhibitors.

XPO1 blockade with KPT-330 promotes apoptosis in cutaneous T-cell lymphoma by activating the p53–p21 and p27 pathways

Dysregulated nuclear-cytoplasmic trafficking has been shown to play a role in oncogenesis in several types of solid tumors and hematological malignancies. Exportin 1 (XPO1) is responsible for the nuclear export of several proteins and RNA species, mainly tumor suppressors. KPT-330, a small molecule inhibitor of XPO1, is approved for treating relapsed multiple myeloma and diffuse large B-cell lymphoma. Cutaneous T-cell lymphoma (CTCL) is an extranodal non-Hodgkin lymphoma with an adverse prognosis and limited treatment options in advanced stages. The effect of therapeutically targeting XPO1 with KPT-330 in CTCL has not been established. We report that XPO1 expression is upregulated in CTCL cells. KPT-330 reduces cell proliferation, induces G1 cell cycle arrest and apoptosis. RNA-sequencing was used to explore the underlying mechanisms. Genes associated with the cell cycle and the p53 pathway were significantly enriched with KPT-330 treatment. KPT-330 suppressed XPO1 expression, upregulated p53, p21WAF1/Cip1, and p27Kip1 and their nuclear localization, and downregulated anti-apoptotic protein (Survivin). The in vivo efficacy of KPT-330 was investigated using a bioluminescent xenograft mouse model of CTCL. KPT-330 blocked tumor growth and prolonged survival (p < 0.0002) compared to controls. These findings support investigating the use of KPT-330 and next-generation XPO1 inhibitors in CTCL.