kpt-276 and Lymphoma--Non-Hodgkin

The chromosomal region maintenance 1 (CRM1) may serve as a novel target for cancer treatment. Here, we investigated the anti non-Hodgkin lymphoma (NHL) activity of two novel CRM1 inhibitors (KPT-185 and KPT-276) in vitro and in vivo. KPT-185 displayed potent antiproliferative properties and induced cell-cycle arrest and apoptosis in several NHL cell lines and patients' tumor cells. The antitumor activity mainly consisted of inducing caspase cleavage and downregulating the expression of antiapoptotic proteins such as CRM1, nuclear factor-κB, and survivin. Furthermore, oral administration of KPT-276 significantly suppressed tumor growth in mice with Jeko-1 xenograft without any major toxic effects.

Topics: Acrylamides; Acrylates; Animals; Antineoplastic Agents; Caspases; Cell Cycle Checkpoints; Down-Regulation; Exportin 1 Protein; Gene Expression Regulation, Neoplastic; Humans; Jurkat Cells; Karyopherins; Lymphoma, Non-Hodgkin; Mice; Mice, Inbred NOD; Mice, SCID; Neoplasm Proteins; Proteolysis; Receptors, Cytoplasmic and Nuclear; Thiazoles; Triazoles; Xenograft Model Antitumor Assays

In previous studies we demonstrated that targeting the nuclear exporter protein exportin-1 (CRM1/XPO1) by a selective inhibitor of nuclear export (SINE) compound is a viable therapeutic strategy against Non-Hodgkin Lymphoma (NHL). Our studies along with pre-clinical work from others led to the evaluation of the lead SINE compound, selinexor, in a phase 1 trial in patients with CLL or NHL (NCT02303392). Continuing our previous work, we studied combinations of selinexor-dexamethasone (DEX) and selinexor-everolimus (EVER) in NHL. Combination of selinexor with DEX or EVER resulted in enhanced cytotoxicity in WSU-DLCL2 and WSU-FSCCL cells which was consistent with enhanced apoptosis. Molecular analysis showed enhancement in the activation of apoptotic signaling and down-regulation of XPO1. This enhancement is consistent with the mechanism of action of these drugs in that both selinexor and DEX antagonize NF-κB (p65) and mTOR (EVER target) is an XPO1 cargo protein. SINE compounds, KPT-251 and KPT-276, showed activities similar to CHOP (cyclophosphamide-hydroxydaunorubicin-oncovin-prednisone) regimen in subcutaneous and disseminated NHL xenograft models in vivo. In both animal models the anti-lymphoma activity of selinexor is enhanced through combination with DEX or EVER. The in vivo activity of selinexor and related SINE compounds relative to 'standard of care' treatment is consistent with the objective responses observed in Phase I NHL patients treated with selinexor. Our pre-clinical data provide a rational basis for testing these combinations in Phase II NHL trials.

Topics: Acrylamides; Active Transport, Cell Nucleus; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Cell Line, Tumor; Cell Survival; Cyclophosphamide; Dexamethasone; Dose-Response Relationship, Drug; Doxorubicin; Drug Synergism; Everolimus; Exportin 1 Protein; Humans; Hydrazines; Karyopherins; Lymphoma, Non-Hodgkin; Mice, Inbred ICR; Mice, SCID; Oxadiazoles; Prednisone; Protein Kinase Inhibitors; Receptors, Cytoplasmic and Nuclear; Signal Transduction; Thiazoles; Time Factors; TOR Serine-Threonine Kinases; Transcription Factor RelA; Triazoles; Tumor Burden; Vincristine; Xenograft Model Antitumor Assays