selinexor and carfilzomib

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Humans; Multiple Myeloma

Proteasome inhibitors (PIs), including carfilzomib, potentiate the activity of selinexor, a novel, first-in-class, oral selective inhibitor of nuclear export (SINE) compound, in preclinical models of multiple myeloma (MM).. The safety, efficacy, maximum-tolerated dose (MTD) and recommended phase 2 dose (RP2D) of selinexor (80 or 100 mg) + carfilzomib (56 or 70 mg/m. Thirty-two patients, median prior therapies 4 (range, 1-8), were enrolled. MM was triple-class refractory in 38% of patients and 53% of patients had high-risk cytogenetics del(17p), t(4;14), t(14;16) and/or gain 1q. Common treatment-related adverse events (all/Grade 3) were thrombocytopenia 72%/47% (G3 and G4), nausea 72%/6%, anaemia 53%/19% and fatigue 53%/9%, all expected and manageable with supportive care and dose modifications. MTD and RP2D were identified as selinexor 80 mg, carfilzomib 56 mg/m. Weekly XKd is highly effective and well-tolerated. These data support further investigation of XKd in patients with MM.

Topics: Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Drug Administration Schedule; Female; Humans; Hydrazines; Male; Maximum Tolerated Dose; Middle Aged; Multiple Myeloma; Oligopeptides; Survival Analysis; Translocation, Genetic; Treatment Outcome; Triazoles

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Cytogenetic Analysis; Dexamethasone; Drug Resistance, Neoplasm; Female; Humans; Hydrazines; Male; Middle Aged; Multiple Myeloma; Neoplasm Staging; Oligopeptides; Prognosis; Recurrence; Retreatment; Treatment Outcome; Triazoles

Proteasome inhibitors, such as bortezomib and carfilzomib, have shown efficacy in anti-cancer therapy in hematological diseases but not in solid cancers. Here, we found that liposarcomas (LPS) are susceptible to proteasome inhibition, and identified drugs that synergize with carfilzomib, such as selinexor, an inhibitor of XPO1-mediated nuclear export. Through quantitative nuclear protein profiling and phospho-kinase arrays, we identified potential mode of actions of this combination, including interference with ribosome biogenesis and inhibition of pro-survival kinase PRAS40. Furthermore, by assessing global protein levels changes, FADS2, a key enzyme regulating fatty acids synthesis, was found down-regulated after proteasome inhibition. Interestingly, SC26196, an inhibitor of FADS2, synergized with carfilzomib. Finally, to identify further combinational options, we performed high-throughput drug screening and uncovered novel drug interactions with carfilzomib. For instance, cyclosporin A, a known immunosuppressive agent, enhanced carfilzomib's efficacy in vitro and in vivo. Altogether, these results demonstrate that carfilzomib and its combinations could be repurposed for LPS clinical management.

Topics: Antineoplastic Combined Chemotherapy Protocols; Bortezomib; Cell Line, Tumor; Cell Nucleus; Drug Resistance, Neoplasm; Drug Synergism; Exportin 1 Protein; Fatty Acid Desaturases; Gene Expression Regulation, Neoplastic; Humans; Hydrazines; Karyopherins; Liposarcoma; Oligopeptides; Piperazines; Proteasome Endopeptidase Complex; Proteasome Inhibitors; Receptors, Cytoplasmic and Nuclear; Triazoles

Topics: Antineoplastic Combined Chemotherapy Protocols; Dexamethasone; Hematopoietic Stem Cell Transplantation; Humans; Hydrazines; Male; Multiple Myeloma; Neoplasm Recurrence, Local; Oligopeptides; Transplantation, Homologous; Treatment Outcome; Triazoles

Topics: Animals; Apoptosis; Cell Line, Tumor; Cell Nucleus; Cell Survival; Exportin 1 Protein; Humans; Hydrazines; I-kappa B Proteins; Inhibitor of Apoptosis Proteins; Karyopherins; Mice; NF-kappa B; Oligopeptides; Receptors, Cytoplasmic and Nuclear; Sarcoma; Survivin; Transcription Factor RelA; Triazoles; Xenograft Model Antitumor Assays

Exportin1 (XPO1; also known as chromosome maintenance region 1, or CRM1) controls nucleo-cytoplasmic transport of most tumor suppressors and is overexpressed in many cancers, including multiple myeloma, functionally impairing tumor suppressive function via target mislocalization. Selective inhibitor of nuclear export (SINE) compounds block XPO1-mediated nuclear escape by disrupting cargo protein binding, leading to retention of tumor suppressors, induction of cancer cell death, and sensitization to other drugs. Combined treatment with the clinical stage SINE compound selinexor and the irreversible proteasome inhibitor (PI) carfilzomib induced synergistic cell death of myeloma cell lines and primary plasma cells derived from relapsing/refractory myeloma patients and completely impaired the growth of myeloma cell line-derived tumors in mice. Investigating the details of SINE/PI-induced cell death revealed (i) reduced Bcl-2 expression and cleavage and inactivation of Akt, two prosurvival regulators of apoptosis and autophagy; (ii) intracellular membrane-associated aggregation of active caspases, which depended on caspase-10 protease activity; and (iii) novel association of caspase-10 and autophagy-associated proteins p62 and LC3 II, which may prime activation of the caspase cascade. Overall, our findings provide novel mechanistic rationale behind the potent cell death induced by combining selinexor with carfilzomib and support their use in the treatment of relapsed/refractory myeloma and potentially other cancers.

Topics: Animals; Antineoplastic Agents; Apoptosis; Autophagy; Caspase 10; Caspase 8; Cell Line, Tumor; Disease Models, Animal; Drug Synergism; Enzyme Activation; Humans; Hydrazines; Intracellular Space; Mice; Multiple Myeloma; Oligopeptides; Proteasome Inhibitors; Triazoles; Xenograft Model Antitumor Assays

Acquired proteasome-inhibitor (PI) resistance is a major obstacle in the treatment of multiple myeloma (MM). We investigated whether the clinical XPO1-inhibitor selinexor, when combined with bortezomib or carfilzomib, could overcome acquired resistance in MM. PI-resistant myeloma cell lines both in vitro and in vivo and refractory myeloma patient biopsies were treated with selinexor/bortezomib or carfilzomib and assayed for apoptosis. Mechanistic studies included NFκB pathway protein expression assays, immunofluorescence microscopy, ImageStream flow-cytometry, and proximity-ligation assays. IκBα knockdown and NFκB activity were measured in selinexor/bortezomib-treated MM cells. We found that selinexor restored sensitivity of PI-resistant MM to bortezomib and carfilzomib. Selinexor/bortezomib treatment inhibited PI-resistant MM tumor growth and increased survival in mice. Myeloma cells from PI-refractory MM patients were sensitized by selinexor to bortezomib and carfilzomib without affecting non-myeloma cells. Immunofluorescence microscopy, Western blot, and ImageStream analyses of MM cells showed increases in total and nuclear IκBα by selinexor/bortezomib. Proximity ligation found increased IκBα-NFκB complexes in treated MM cells. IκBα knockdown abrogated selinexor/bortezomib-induced cytotoxicity in MM cells. Selinexor/bortezomib treatment decreased NFκB transcriptional activity. Selinexor, when used with bortezomib or carfilzomib, has the potential to overcome PI drug resistance in MM. Sensitization may be due to inactivation of the NFκB pathway by IκBα.

Topics: Active Transport, Cell Nucleus; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Bortezomib; Cell Line, Tumor; Cell Nucleus; Dose-Response Relationship, Drug; Drug Resistance, Neoplasm; Exportin 1 Protein; Female; Gene Expression Regulation, Neoplastic; Humans; Hydrazines; Karyopherins; Mice, Inbred NOD; Mice, SCID; Multiple Myeloma; NF-kappa B; NF-KappaB Inhibitor alpha; Oligopeptides; Proteasome Endopeptidase Complex; Protein Stability; Proteolysis; Receptors, Cytoplasmic and Nuclear; RNA Interference; Time Factors; Transcription, Genetic; Transfection; Triazoles; Xenograft Model Antitumor Assays