eltanexor (KPT-8602)

P1, N=60, Not yet recruiting, Vanderbilt-Ingram Cancer Center

P1/2, N=15, Terminated, Shanghai Antengene Corporation Limited | N=59 --> 15 | Trial completion date: Mar 2024 --> Sep 2023 | Active, not recruiting --> Terminated; The study was stopped early because the sponsor decided to change the study-drug development strategy

Adjuvant treatment for Glioblastoma Grade 4 with Temozolomide (TMZ) inevitably fails due to therapeutic resistance, necessitating new approaches...We assessed TMZ, Methotrexate (MTX), and Cytarabine (Ara-C) (apoptosis inducers) combined with XPO1/Bcl-2/Mcl-1-inhibitors (apoptosis rescue) in GB cell lines and primary GB stem-like cells (GSCs)...TMZ, MTX, and Ara-C combined with E, V, and A evidenced highly lethal effects when combined. As no significant cell death induction in mouse brain slices was observed, we conclude that this drug combination is effective in vitro and expected to have low side effects in vivo.

P1/2, N=277, Active, not recruiting, Karyopharm Therapeutics Inc | Trial completion date: Aug 2024 --> Dec 2024

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.

P1/2, N=80, Recruiting, National Cancer Institute (NCI) | Not yet recruiting --> Recruiting

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. 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.

The two XPO1 inhibitors (Selinexor and Eltanexor) included in our drug panel were within the four top-ranked compounds. This study offers valuable insights into the molecular and pathological mechanisms underlying t(6; 9)-AML, revealing a functional interaction between DEK-NUP214, XPO1 and FOXC1, and providing evidence to consider XPO1 inhibition as a potential new avenue to treat these patients.

Nine compounds with known XPO1 inhibitory effect including five synthetic (KPT-185, KPT-276, KPT-330 or selinexor, KPT-335 or verdinexor and KPT-8602 or eltanexor) and four natural active compounds (curcumin, oridonin, piperlongumine and plumbagin) were evaluated in patient-derived HSPCs (n=1) for their potency and efficacy. Therefore, repurposing of selinexor to improve ineffective erythropoiesis in β-thalassemia is compelling. Moreover, combination treatments of selinexor with HbF inducers and/or SMAD2/3 blockers could be further validated to possibly achieve greater therapeutic benefits for β-thalassemia treatments.

Previous findings from a phase 2 clinical trial of the XPO1 inhibitor selinexor in patients with high-risk myelodysplastic syndrome (MDS) relapsed or refractory to hypomethylating agents (HMA) revealed increased activity in patients with SF3B1 mutations...Using the Bliss independence model to calculate synergy, we identifed two drugs that greatly synergized with eltanexor specifically in the SF3B1 mutant cell lines: venetoclax (a BCL2 inhibitor), and navitoclax (a BCL2/BCL-XL inhibitor)...Our findings may also contribute to the development of potentially synergistic therapeutic combinations. In this regard, recent human data have shown that venetoclax can overcome the poor prognosis of spliceosomal mutant AML patients (Senapati et al, Blood 2023); therefore, combining eltanexor with venetoclax could represent a promising SF3B1-specific therapy.

This study demonstrated that the BET antagonist INCB057643 synergized with the XPO1 inhibitors (selinexor and eltanexor) to decrease cell viability and increase cell apoptosis in HGBCL-DH cells with or without TP53 mutations. Collectively, we might provide a potential promising combination therapy regimen for the management of HGBCL-DH. Clinical evaluations are warranted to confirm this conclusion.

P1/2, N=277, Active, not recruiting, Karyopharm Therapeutics Inc | Recruiting --> Active, not recruiting

P1/2, N=100, Not yet recruiting, National Cancer Institute (NCI)

Eltanexor showed a stronger effect than Selinexor potently inducing PARP cleavage. Consistently with in vitro data, we observed that selinexor impaired tumor growth in vivo, both in EML4-ALK transgenic mice and in ALK TKI-resistant xenograft tumors in mice.ConclusionThese data support the therapeutic value of SINEs alone or in combination with ALK-TKIs for the treatment of ALK+NSCLCs, even after their loss of responsiveness to targeted therapy and regardless of their p53 mutational status.

We found that the exportin 1 (XPO1) inhibitors, selinexor and eltanexor, selectively kill tet2-mutant HSPCs. Selective killing of TET2-mutant HSPCs and human AML cells by these inhibitors was due to increased levels of apoptosis, without evidence of DNA damage based on increased γH2AX expression. The finding that TET2 loss renders HSPCs and AML cells selectively susceptible to cell death induced by XPO1 inhibitors provides preclinical evidence of the selective activity of these drugs, justifying further clinical studies of these small molecules for the treatment of TET2-mutant haematopoietic malignancies, and to suppress clonal expansion in age-related TET2-mutant clonal haematopoiesis.

In KPC-tumor-derived cell lines, selinexor or second-generation analog eltanexor inhibited cell growth and suppressed spheroid formation. In spatial transcriptomic analysis, marked suppression of stroma supporting markers was observed in tumor and stromal compartments. Collectively, our studies show that XPO1 is a valid therapeutic target in PDAC and Sel-GemPac is an effective combination that inhibits growth and regulates the tumor microenvironment.

Although XPO1 has a central role in cellular homeostasis, it is a good target for cancer therapy, as illustrated by the clinical success of the selective inhibitor of nuclear export (SINE) selinexor...The second generation SINE eltanexor is also a covalent XPO1 inhibitor but has only minimal brain penetration and consequently lower toxicity in preclinical studies...Importantly, it shows potent efficacy in both an orthotopic U87 MG brain tumor xenograft model and a metastatic syngeneic ID8-fLuc ovarian cancer model with significant survival benefit as monotherapy. Altogether, these results demonstrate that FR-027 is a novel, reversible XPO1 inhibitor with important molecular and pharmacological characteristics that warrant further clinical development.

These results highlighted the therapeutic value of targeting XPO1 in overcoming sorafenib resistance. The combinational treatment of KPT-8602 and sorafenib might be an improved therapeutic option.

We report on a novel systems-biology-based comparative framework to identify non-genetically encoded vulnerabilities in genomically quiescent pediatric cancers. These results have provided preclinical rationale for investigation of XPO1 inhibitors in an upcoming investigator-initiated clinical trial of selinexor in children with MRTs and WTs and offer opportunities for exploration of inferred XPO1 activity as a potential predictive biomarker for response.

Cell viability, induction of apoptosis, cell cycle and proliferation were measured at 24h, 72h and 96h for FKH-1 cells after single treatment with eltanexor and cytarabine. DEK-NUP214 positive FKH-1 cells are sensitive to CRM1 inhibition by eltanexor, which downregulates putative gene targets of DEK-NUP214 leukemia. We have successfully established a DEK-NUP214 PDX model and show exceptional sensitivity of these cells to eltanexor in vivo.

Treatment with XPO1 inhibitors (Selinexor and Eltanexor) resulted in rapid relocalization of cytoplasmic NPM1c to the nucleus. To that end, we explore relevant fusion proteins found in hematological malignancies and assess their capacity for driving condensates that activate HOX transcription. Altogether, our results suggest that nuclear phase separation, driven by NPM1c or other HOX-associated drivers, is a ubiquitous mechanism underlying AML, providing a solid foundation for developing new therapeutics targeting common vulnerabilities across AML subtypes.

To determine whether XPO1 can be therapeutically exploited in TP53-MNs, we performed in vitro viability assays with increasing doses of eprenetapopt and the XPO1 inhibitor selinexor and the second generation eltanexor. Our data collectively suggest that XPO1 is overexpressed after eprenetapopt and 5-azacitidine treatment resulting in re-folded TP53 being shuttled to the cytoplasm leading to therapeutic resistance. Patient derived xenograft assays testing this novel combination therapy in vivo with TP53-MN primary samples are underway and will be presented during the ASH meeting.

This study demonstrates that prolonged XPO1 inhibition is necessary to achieve optimal antileukemic activity and lays the groundwork for the design of new clinical trials with XPO1 inhibitors in NPM1c AML.

Immunofluorescence of GBM cell lines treated with Eltanexor revealed a strong accumulation of CDKN1A, and, to a lesser extent, of p53 and Tp53i3 in cell nuclei as a plausible mechanism for Eltanexor-induced apoptosis. From these data, we conclude that monotherapy with Eltanexor effectively induces apoptosis in GBM cells and can be combined with current adjuvant therapies to provide a more effective therapy of GBM.

XPO1 inhibition by selinexor (seli) leads to NPM1c nuclear relocalization, loss of HOX expression, and terminal differentiation...Since the newer XPO1 inhibitor eltanexor (elta) is given 5 days/week in early-phase clinical studies, we compared the antileukemic effects of intermittent (2d/w) and prolonged (5d/w) XPO1 inhibition in NPM1c AML models... This study demonstrates that prolonged XPO1 inhibition is necessary to achieve optimal antileukemic activity and lays the groundwork for the design of new clinical trials with XPO1 inhibitors in NPM1c AML.

Selinexor and eltanexor are selective inhibitors of nuclear export (SINE) that prevent the karyopherin protein exportin-1 (XPO1) from shuttling its cargo proteins through nuclear pore complexes out of the nucleus and into the cytoplasm...Here we demonstrate the preclinical effectiveness of SINE compounds used as single agents or in combination with either the proteasome inhibitor, bortezomib, or the CDK4/6 inhibitor, abemaciclib, against various patient- derived xenograft (PDX) mouse models of chordoma, which included clival and sacral chordomas from adult or pediatric patients with either primary or metastatic disease, with either differentiated or poorly differentiated subtypes...This is consistent with SINE-compound mediated XPO1 inhibition exhibiting anti-cancer activity through a broad range of different mechanisms in different molecular chordoma subsets. Our findings validate the need for further investigation into selinexor as a targeted therapeutic for chordoma, especially in combination with abemaciclib.

Although there is a rationale for using XPO1 inhibitors in NPM1-mutated AML, selinexor administered once or twice per week did not translate into clinical benefit in NPM1-mutated patients. Eltanexor caused irreversible HOX downregulation, induced terminal AML differentiation and prolonged survival of leukemic mice. This study provides essential information for the appropriate design of clinical trials with XPO1 inhibitors in NPM1-mutated AML.

In mechanism, KPT-8602 restored the localization of cytoplasmic FOXO3A, p27, p21, IκBα and PP2A into the nucleus, leading to AKT and NF-κB deactivation. Our data demonstrate for the first time that XPO1 could be an unfavorable prognostic factor for TCL, and provide a rationale for further investigation of the efficacy of KPT-8602 in TCL patients.

In this study, using real-time RT-PCR and Western blot analysis, we show that inhibition of XPO1 via KPT-330 or KPT-8602 (Eltanexor) decreases the mRNA and protein levels of c-Myc, CHK1, WEE1, RAD51 and RRM2. This study provides new insight into the molecular mechanism underlying the synergistic antileukaemic activity between venetoclax and XPO1 inhibitors against AML. Our data support the clinical evaluation of this promising combination therapy for the treatment of AML.

Some LR-MDS patient subgroups may also benefit from specific therapies including luspatercept (MDS with ring sideroblasts), lenalidomide (MDS with deletion 5q), or immunosuppressive therapy (hypocellular MDS)...Despite promising novel combinations, the HMAs azacitidine (AZA) or decitabine (DAC) are still the standard of care for these patients, with intensive chemotherapy-based approaches being a potential option in a small subset of patients...Experimental agents to consider include venetoclax, myeloid cell leukemia 1 (MCL-1) inhibitors, eprenetapopt, CPX-351, immunotherapies (directed towards CD47, TIM3, or CD70), interleukin-1 receptor-associated kinase 4 (IRAK4) inhibitors, pevonedistat, seclidemstat, and eltanexor. In this review, we extensively discuss the current landscape of experimental therapies for both LR- and HR-MDS.

In vivo treatment of panel of MRT and WT CDX and PDX models with selinexor and a next-generation XPO1 inhibitor, eltanexor, resulted in significant abrogation of tumor growth with associated decreases in inferred XPO1 activity. XPO1 represents a non-genetically encoded vulnerability in MRT and WT. Promising preclinical activity in MRT and WT models has provided the preclinical rationale for evaluation of XPO1 inhibition in an investigator-initiated clinical trial of Selinexor in pediatric MRT and WT.

The registrational phase III BOSTON trial demonstrated the superiority of selinexor in combination with bortezomib and dexamethasone as compared with bortezomib and dexamethasone in patients with relapsed refractory multiple myeloma (RRMM) who have received one to three prior anti-MM regimens. Eltanexor is an investigational SINE compound that has shown a more positive toxicity profile in preclinical studies, with reduced central nervous system penetration and gastrointestinal side effects, and is now undergoing clinical investigation. These and other trials will further clarify the role of these innovative agents in the therapeutic advancement of RRMM.

We also showed that a selective inhibitor of nuclear export (SINE) selinexor and second generation eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with PARP inhibitors (PARPi) olaparib, veliparib and rucaparib in 22rv1 mCRPC cells...KPT-8602 with or without olaparib was shown to reduce homologous recombination-regulated DNA damage response targets including BRCA1, BRCA2, CHEK1, EXO1, BLM, RAD51, LIG1, XRCC3 and RMI2. Taken together, this study revealed the therapeutic potential of a novel combination of KPT-8602 and PARP inhibitors for the treatment of mCRPC.

These data demonstrate that the antileukemic effect of PSEN1-selective gamma-secretase inhibition can be synergistically enhanced by the addition of other targeted inhibitors. The combination of MRK-560 with KPT-8602 is a highly effective treatment combination, which circumvents the need for the identification of additional mutations and provides a clear survival benefit in vivo. These promising preclinical data warrant further development of combination treatment strategies for T-ALL based on PSEN1-selective gamma-secretase inhibition.

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).

Our findings anticipate tremendous therapeutic benefit and support the further evaluation of XPO1 inhibitors, especially in combination with DNA damage checkpoint inhibitors, to elicit an enduring clinical response in patients with CRC harboring TP53 mutations.

We also showed that the selective inhibitor of nuclear export (SINE) compound selinexor and the second generation SINE eltanexor (KPT-8602) could suppress mCRPC growth, reduce androgen receptor (AR), and re-sensitize to androgen deprivation therapy. Here we evaluated the combination of KPT-8602 with three different PARP inhibitors (PARPi) namely olaparib, veliparib and rucaparib in a mCRPC model...Interestingly, KPT-8602 with or without the PARPi olaparib was shown to reduce homologous recombination (HR) regulated DNA damage response (DDR) targets including BRCA1, BRCA2, BLM, XRCC3, EXO1, RMI1, RMI2, RAD54L, CHEK1, LIG1 and RAD51 (P < 0.01).Taken together, this study revealed the therapeutic potential of a novel combination including second generation SINE compound KPT-8602 and PARP inhibitors for the growth inhibition of mCRPC cells. Pre-clinical xenograft studies testing the efficacy of SINE-PARPi as well as a phase II clinical study combining KPT-8602-PARPi is planned.

As a result, nuclear accumulation of p62 increased expression of innate immune-related genes including IRF7, ISG15, IFIT1, IFIT2, and IFIT3, leading to a reduction of KSHV lytic replication. These results illustrate a novel mechanism by which XPO1 mediates innate immune response and KSHV replication, and identify XPO1 as a potential therapeutic target and KPT-8602 as a promising therapeutic agent for KSHV infection.

Collectively, t(6;9) primary samples also showed a selective drug sensitivity to XPO1 (selinexor and eltanexor) and JAK inhibitors (ruxolitinib, tofacitinib and momelotinib) compared to other cytogenetic risk groups. On the other hand, a comparison of in vitro drug sensitivity data with genomic data of our entire cohort of patients demonstrated that TP53 wt AMLs (n=37) were more sensitive to all four MDM2 inhibitors (AMG-232, idasanutlin, SAR405838 and NVP-CGM097) compared to TP53 mutated cases (n=13). Comparisons of transcriptomics with the in vitro sensitivity to drugs included in early/late phase AML clinical trials, identified signatures of response associated with MDM2 and Aurora B kinase (AZD1152-HQPA) inhibitors...Functionally, group A presented with elevated HOXA10 protein expression and enhanced in vitro response to genotoxic drugs and cell cycle inhibitors when compared to group B leukemia. Conclusions : Our study demonstrates the feasibility of simultaneously generating omics data from several different platforms and highlights that a combination of genetic and proteomic profiles may help to inform the choice of therapies based on the underlying biology of a patient’s AML.