In vitro application of the CDK9 inhibitor AZD4573 and XPO1 inhibitor Selinexor significantly reduced DLBCL cell line viability as single agents and produced synergistic results when applied in combination. Our analysis presents key associations between the MYC oncogene and depleted TME presence capable of providing clarity within the evolving precision CAR-T treatment landscape.

This study demonstrates the enhanced efficacy of XPO1-targeted therapy through the inhibition of the Wnt/β-catenin signaling pathway and introduces XPinβ, a proteinoid microsphere with promising clinical translational potential for dual targeting therapy against melanoma involving both XPO1 and β-catenin.

P=N/A, N=30, Recruiting, Tianjin Medical University Cancer Institute and Hospital

In summary, selinexor in combination with decitabine has significant synergistic effects both in vitro and in vivo and represents a new treatment option for RR T-LBL.

P2, N=96, Suspended, Hackensack Meridian Health | Trial completion date: Jan 2025 --> Jan 2026 | Recruiting --> Suspended | Trial primary completion date: Jan 2025 --> Jan 2026

However, for SARS-CoV-2, Selinexor treatment had diverse effects on virus replication in different cell lines. These results indicate that XPO1-mediated nuclear export pathway inhibition might affect coronavirus replication depending on cell types and virus origin.

A recent randomized study of intensive chemotherapy with and without the Exportin inhibitor selinexor in elderly patients showed reduced survival in the selinexor arm; this was due to a high frequency of relapse and severe infections during neutropenia. Experimental studies suggest that Exportin 1 inhibition can be combined with other forms of targeted therapy. Thus, Exportin 1 inhibition should still be regarded as a promising strategy for AML treatment, but future studies should focus on the risk of toxicity when combined with conventional chemotherapy, especially in elderly/unfit patients, combinations with targeted therapies, identification of patient subsets (AML is a heterogeneous disease) with high susceptibility, and the possible use of less toxic next-generation Exportin 1 inhibitors.

Selinexor-related toxicities were primarily hematologic and neurologic requiring dose or dose-frequency reduction. The MTD and recommended initial phase 2 dose of selinexor in children and adolescents with recurrent solid and CNS tumors is 35 mg/m2/dose QW.

P2, N=18, Active, not recruiting, University of Colorado, Denver | Trial completion date: Nov 2025 --> Nov 2026 | Trial primary completion date: Aug 2024 --> Aug 2026

SEL in combination with NIVO or NIVO+IPI had a potentially favorable safety profile and showed modest clinical activity in patients with advanced renal cell carcinoma.

P2, N=15, Recruiting, University of Rochester | Trial completion date: Dec 2024 --> Dec 2025

P2, N=27, Not yet recruiting, Duke University

P3, N=150, Active, not recruiting, Antengene Corporation | Trial completion date: Oct 2024 --> Dec 2025 | Trial primary completion date: Jul 2024 --> Dec 2025

P=N/A, N=20, Active, not recruiting, Durham VA Medical Center | Not yet recruiting --> Active, not recruiting

P2, N=60, Completed, Antengene Corporation | Active, not recruiting --> Completed

This work demonstrates that XPO1 inhibitor KPT-330 in combination with CDK4/6 inhibitor additively suppressed BLBC tumor growth in vivo. These results reveal a novel positive feedback regulation loop between KLF5 and XPO1 and provide a novel treatment strategy for BLBC.

Given the difficulty in targeting c-Myc directly, this work tests selinexor and vorinostat in SCLC xenograft models, with selinexor showing superior results. High HDAC7 expression is linked to increased SCLC proliferation, poorer prognosis, and enhanced sensitivity to selinexor in SCLC cell lines and organoid models. Collectively, this work uncovers a novel HDAC7/c-Myc/XPO1 signaling axis that promotes SCLC progression, suggesting that HDAC7 may warrant further investigation as a potential biomarker for assessing selinexor sensitivity in SCLC patients.

T-PLL cells exhibited a particular sensitivity to drugs targeting autophagy (thapsigargin, bafilomycin A1), nuclear export (selinexor), and inhibitor of apoptosis proteins (IAPs) (birinapant), sensitivities that were also shared by other T-cell malignancies. Through spectral flow cytometry we confirmed the absence of cleaved caspase-3 in IAP inhibitor treated T-PLL cells and show that IAP inhibition reduces the proliferation of T-PLL cells stimulated ex-vivo, while showing only a limited effect on non-malignant T-cells. In summary, our study maps the drug sensitivity of T-PLL across a broad range of targets and identifies new therapeutic approaches for T-PLL by targeting IAPs, XPO1 and autophagy, highlighting potential candidates for drug repurposing and novel treatment strategies.

In our efforts to enhance sensitivity to PARP inhibitors, we identified clofarabine (CLF) as a potential therapy for drug-resistant ovarian cancer and nuclear trafficking of Cathepsin L (CTSL) as a treatment- responsive biomarker. Using PARP inhibitor-sensitive and -resistant OC cell lines, ex vivo cultures of patient-derived ovarian ascites (OVA), primary ovarian tumors, and xenografts (PDX), we found that CLF monotherapy induces nuclear CTSL (nCTSL) in CLF-responsive cells (CLF-r) and sensitizes them to PARP inhibitors olaparib and rucaparib...In these samples, inhibiting CRM1 with KPT8602 restored synergy between CLF and PARP inhibitors. In vivo, CLF-r and CLF-nr PDX models exhibited enhanced DDR, reduced tumor burden, and prolonged survival with the CLF+olaparib combination. These findings suggest the CLF+olaparib combination is a promising therapeutic strategy for drug-resistant OC by inducing DDR through CTSL nuclear localization.

Moreover, CD62L overexpression in a human AML cell line resulted in significantly prolonged survival in a xenograft mouse model. We propose that targeting the STAT3β/α ratio could be a promising new strategy for treating patients with AML and that the combination of selinexor and atovaquone could offer enhanced treatment outcomes.

P2, N=127, Recruiting, Karyopharm Therapeutics Inc | Trial completion date: Jun 2025 --> Jan 2028 | Trial primary completion date: Jun 2024 --> Jan 2028

P2/3, N=501, Recruiting, Karyopharm Therapeutics Inc | Trial primary completion date: Dec 2024 --> Dec 2025

P=N/A, N=55, The First Affiliated Hospital, Zhejiang University School of Medicine; The First Affiliated Hospital, Zhejiang University School of Medicine

P2, N=73, Active, not recruiting, US Oncology Research | Recruiting --> Active, not recruiting

P1, N=30, Recruiting, Oncotherapeutics | Not yet recruiting --> Recruiting

In conclusion, our findings underscore the essential role of XPO1 degradation in the anti-myeloma efficacy of SEL and establish a research foundation for targeting USP7 to improve the effectiveness of SEL-based therapies in MM.

P1, N=59, Completed, Children's Oncology Group | Active, not recruiting --> Completed | Trial completion date: Sep 2025 --> Dec 2024

Interestingly, the combination of eltanexor with gemcitabine showed significant anticancer activity in PDAC cells. Altogether, our findings revealed the crucial role of XPO1 in modulating the expression of oncogenic proteins, ncRNAs, and DNA damage during PDAC progression as well as identified novel therapeutic miR-193b/KRAS/LAMC2/ERK/AKT axis.

P2, N=73, Not yet recruiting, Ruijin Hospital

These results suggest that activation of autophagy confers a protective mechanism against Selinexor in GBM cells, and that the combination of Selinexor with autophagy inhibitors may serve as a viable means to enhance Selinexor-induced cell death.

Selinexor, a XPO1 inhibitor, has shown promising activity in preclinical and clinical studies, particularly in hematological malignancies...Further research is necessary to fully elucidate the molecular landscape according to XPO1 expression in GI tumors and to validate the efficacy of selective XPO1 inhibitors. These efforts are expected to contribute to the development of more effective and personalized therapeutic strategies for GI cancer patients.

P2, N=50, Not yet recruiting, Navy General Hospital, Beijing

P1, N=42, Recruiting, St. Jude Children's Research Hospital | Trial completion date: Jul 2025 --> Jun 2027

This study investigates the potential of repurposing selinexor, an FDA-approved XPO1 inhibitor, as a novel therapeutic options for TNBC... XPO1 inhibitors show promise as targeted therapies for TNBC patients. New mechanistic insight into the causes leading to TNBC sensitivity to XPO1-inhibition-mediated cell death warrant further clinical trials to evaluate the safety and efficacy in TNBC.

Using complementary genetically engineered mouse (GEM) models, we demonstrated that TP53 and/or PTEN deficient TCL, and LAM within their TME, are sensitive to the selective XPO1 antagonist selinexor...We identified a novel role for eIF4E/XPO1 in exporting GATA-3 and GATA-3-dependent transcripts from the nucleus in TCL, and in the export of therapeutically relevant transcripts, including CSF-1R, from LAM. Therefore, XPO1 antagonism, by impairing oncogenic transcriptional programs in TCL and depleting LAM from their TME, is a novel approach to target two independent dependencies in a group of therapeutically challenging TCL.

Selinexor plus docetaxel was relatively well tolerated in patients with advanced KRAS mutant NSCLC. The regimen has promising efficacy in TP53 wild type cases, where selinexor monotherapy may also have activity.

P1, N=16, Active, not recruiting, Dana-Farber Cancer Institute | Trial completion date: Dec 2024 --> Jun 2025

P1, N=100, Recruiting, University of Chicago | Trial completion date: Dec 2024 --> Dec 2025 | Trial primary completion date: Jul 2024 --> Jul 2025

Simultaneously, the intracellular localization of FOXO3 can be monitored by a second cell line stably expressing GFP-FOXO3. Here we describe a detailed protocol on how to co-culture these reporter cell lines and use them to interrogate compound-induced FOXO3 activation in order to understand the mode of action.

P1, N=59, Active, not recruiting, Children's Oncology Group | Trial completion date: Sep 2024 --> Sep 2025

Key findings highlight the effectiveness of selinexor in preclinical studies, particularly against KRAS-mutant NSCLC and in combination with chemotherapy for SCLC. The review concludes with a discussion of future directions and underscores the potential of selinexor to improve the treatment strategies for lung cancer.

P1, N=78, Completed, Sanjay Mohan | Active, not recruiting --> Completed | Trial completion date: Dec 2024 --> Sep 2024