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Purpose: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematologic tumors. We assessed intratumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma., Patients and Methods: Seventy-six adults with Karnofsky Performance Status ≥ 60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) preoperatively (Arm A; n = 8 patients). Patients not undergoing surgery received 50 mg/m 2 (Arm B, n = 24), or 60 mg (Arm C, n = 14) twice weekly, or 80 mg once weekly (Arm D; n = 30). Primary endpoint was 6-month progression-free survival rate (PFS6)., Results: Median selinexor concentrations in resected tumors from patients receiving presurgical selinexor was 105.4 nmol/L (range 39.7-291 nmol/L). In Arms B, C, and D, respectively, the PFS6 was 10% [95% confidence interval (CI), 2.79-35.9], 7.7% (95% CI, 1.17-50.6), and 17% (95% CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% [Arm B, 8.3% (95% CI, 1.0-27.0); C: 7.7% (95% CI, 0.2-36.0); D: 10% (95% CI, 2.1-26.5)], with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; 1 (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%), and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC = 0.88)., Conclusions: At 80 mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma., (©2021 The Authors; Published by the American Association for Cancer Research.)

Purpose: The nuclear exporter protein exportin-1 (XPO1) is overexpressed in non-Hodgkin lymphoma (NHL) and correlates with poor prognosis. We evaluated enhancing R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) activity in NHL by targeted inhibition of XPO1 using the selective inhibitor of nuclear export (SINE) compounds., Patients and Methods: We evaluated the antitumor activity of SINE compounds in combination with CHO chemotherapy in vitro and in vivo . Newly diagnosed NHL patients in a phase I dose-escalation study received R-CHOP for 6 cycles with weekly selinexor (60, 80, and 100 mg), then selinexor maintenance therapy for one year. RT-PCR, Western blotting, and RNA sequencing were performed on patient blood samples., Results: SINE compounds synergized with CHO in vitro in NHL cell lines and in vivo in our murine xenograft model. In our phase I study, selinexor was dosed at 60 mg ( n = 6) and 80 mg ( n = 6). The most common adverse events (AE) among 12 patients were fatigue (67%) and nausea (100%). Grade 3-4 AEs were infrequent. Ten evaluable patients had an overall response rate of 100% and complete remission rate of 90% with sustained remissions (median follow-up: 476 days). Maximally tolerated dose was not reached; however, the recommended phase II dose was 60 mg selinexor weekly after evaluating tolerability and discontinuation rates for each dose cohort. Analysis of patient blood samples revealed downregulation of XPO1 and several prosurvival markers., Conclusions: SINE compounds enhance the activity of CHO in vitro and in vivo . Selinexor in combination with R-CHOP was generally well tolerated and showed encouraging efficacy in NHL (NCT03147885)., (©2021 American Association for Cancer Research.)

Purpose: Human exportin-1 (XPO1) is the key nuclear-cytoplasmic transport protein that exports different cargo proteins out of the nucleus. Inducing nuclear accumulation of these proteins by inhibiting XPO1 causes cancer cell death. First clinical validation of pharmacological inhibition of XPO1 was obtained with the Selective Inhibitor of Nuclear Export (SINE) compound selinexor (KPT-330) demonstrating activity in phase-II/IIb clinical trials when dosed 1 to 3 times weekly. The second-generation SINE compound KPT-8602 shows improved tolerability and can be dosed daily. Here, we investigate and validate the drug-target interaction of KPT-8602 and explore its activity against acute lymphoblastic leukemia (ALL). Experimental Design: We examined the effect of KPT-8602 on XPO1 function and XPO1-cargo as well as on a panel of leukemia cell lines. Mutant XPO1 leukemia cells were designed to validate KPT-8602's drug-target interaction. In vivo , anti-ALL activity was measured in a mouse ALL model and patient-derived ALL xenograft models. Results: KPT-8602 induced caspase-dependent apoptosis in a panel of leukemic cell lines in vitro Using CRISPR/Cas9 genome editing, we demonstrated the specificity of KPT-8602 for cysteine 528 in the cargo-binding groove of XPO1 and validated the drug target interaction. In vivo , KPT-8602 showed potent anti-leukemia activity in a mouse ALL model as well as in patient-derived T- and B-ALL xenograft models without affecting normal hematopoiesis. Conclusions: KPT-8602 is highly specific for XPO1 inhibition and demonstrates potent anti-leukemic activity supporting clinical application of the second-generation SINE compound for the treatment of ALL. Clin Cancer Res; 23(10); 2528-41. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Purpose: The high fatality-to-case ratio of ovarian cancer is directly related to platinum resistance. Exportin-1 (XPO1) is a nuclear exporter that mediates nuclear export of multiple tumor suppressors. We investigated possible clinicopathologic correlations of XPO1 expression levels and evaluated the efficacy of XPO1 inhibition as a therapeutic strategy in platinum-sensitive and -resistant ovarian cancer. Experimental Design: XPO1 expression levels were analyzed to define clinicopathologic correlates using both TCGA/GEO datasets and tissue microarrays (TMA). The effect of XPO1 inhibition, using the small-molecule inhibitors KPT-185 and KPT-330 (selinexor) alone or in combination with a platinum agent on cell viability, apoptosis, and the transcriptome was tested in immortalized and patient-derived ovarian cancer cell lines (PDCL) and platinum-resistant mice (PDX). Seven patients with late-stage, recurrent, and heavily pretreated ovarian cancer were treated with an oral XPO1 inhibitor. Results: XPO1 RNA overexpression and protein nuclear localization were correlated with decreased survival and platinum resistance in ovarian cancer. Targeted XPO1 inhibition decreased cell viability and synergistically restored platinum sensitivity in both immortalized ovarian cancer cells and PDCL. The XPO1 inhibitor-mediated apoptosis occurred through both p53-dependent and p53-independent signaling pathways. Selinexor treatment, alone and in combination with platinum, markedly decreased tumor growth and prolonged survival in platinum-resistant PDX and mice. In selinexor-treated patients, tumor growth was halted in 3 of 5 patients, including one with a partial response, and was safely tolerated by all. Conclusions: Taken together, these results provide evidence that XPO1 inhibition represents a new therapeutic strategy for overcoming platinum resistance in women with ovarian cancer. Clin Cancer Res; 23(6); 1552-63. ©2016 AACR ., (©2016 American Association for Cancer Research.)

Purpose: Selinexor, a selective inhibitor of XPO1, is currently being tested as single agent in clinical trials in acute myeloid leukemia (AML). However, considering the molecular complexity of AML, it is unlikely that AML can be cured with monotherapy. Therefore, we asked whether adding already established effective drugs such as topoisomerase (Topo) II inhibitors to selinexor will enhance its anti-leukemic effects in AML., Experimental Design: The efficacy of combinatorial drug treatment using Topo II inhibitors (idarubicin, daunorubicin, mitoxantrone, etoposide) and selinexor was evaluated in established cellular and animal models of AML., Results: Concomitant treatment with selinexor and Topo II inhibitors resulted in therapeutic synergy in AML cell lines and patient samples. Using a xenograft MV4-11 AML mouse model, we show that treatment with selinexor and idarubicin significantly prolongs survival of leukemic mice compared with each single therapy., Conclusions: Aberrant nuclear export and cytoplasmic localization of Topo IIα has been identified as one of the mechanisms leading to drug resistance in cancer. Here, we show that in a subset of patients with AML that express cytoplasmic Topo IIα, selinexor treatment results in nuclear retention of Topo IIα protein, resulting in increased sensitivity to idarubicin. Selinexor treatment of AML cells resulted in a c-MYC-dependent reduction of DNA damage repair genes (Rad51 and Chk1) mRNA and protein expression and subsequent inhibition of homologous recombination repair and increased sensitivity to Topo II inhibitors. The preclinical data reported here support further clinical studies using selinexor and Topo II inhibitors in combination to treat AML. Clin Cancer Res; 22(24); 6142-52. ©2016 AACR., Competing Interests: Conflict of Interests T.K, Y.L, M.K and S.S are employees of Karyopharm therapeutics, a clinical stage biopharmaceutical company that develops selective inhibitors of nuclear export-targeted therapeutics., (©2016 American Association for Cancer Research.)

Purpose: Combination of radiation with radiosensitizing chemotherapeutic agents improves outcomes for locally advanced rectal cancer. Current treatment includes 5-fluorouracil-based chemoradiation prior to surgical resection; however pathologic complete response varies from 15% to 20%, prompting the need to identify new radiosensitizers. Exportin 1 (XPO1, also known as chromosome region 1, CRM1) mediates the nuclear export of critical proteins required for rectal cancer proliferation and treatment resistance. We hypothesize that inhibition of XPO1 may radiosensitize cancer cells by altering the function of these critical proteins resulting in decreased radiation resistance and enhanced antitumoral effects., Experimental Design: To test our hypothesis, we used the selective XPO1 inhibitor, selinexor, to inhibit nuclear export in combination with radiation fractions similar to that given in clinical practice for rectal cancer: hypofractionated short-course radiation dosage of 5 Gy per fraction or the conventional long-course radiation dosage of 1 Gy fractions. Single and combination treatments were tested in colorectal cancer cell lines and xenograft tumor models., Results: Combination treatment of radiotherapy and selinexor resulted in an increase of apoptosis and decrease of proliferation compared with single treatment, which correlated with reduced tumor size. We found that the combination promoted nuclear survivin accumulation and subsequent depletion, resulting in increased apoptosis and enhanced radiation antitumoral effects., Conclusions: Our findings suggest a novel therapeutic option for improving radiation sensitivity in the setting of rectal cancer and provide the scientific rationale to evaluate this combination strategy for clinical trials., (©2015 American Association for Cancer Research.)