Anti-tumor activity of selective inhibitor of nuclear export (SINE) compounds, is enhanced in non-Hodgkin lymphoma through combination with mTOR inhibitor and dexamethasone.
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.
Department of Oncology, Wayne State University, USA.
Irfana
I
Muqbil
Department of Oncology, Wayne State University, USA.
Amro
A
Aboukameel
Karyopharm Therapeutics Inc, Newton, MA, USA.
Sivan
S
Elloul
Karyopharm Therapeutics Inc, Newton, MA, USA.
Robert
R
Carlson
Karyopharm Therapeutics Inc, Newton, MA, USA.
William
W
Senapedis
Karyopharm Therapeutics Inc, Newton, MA, USA.
Erkan
E
Baloglu
Karyopharm Therapeutics Inc, Newton, MA, USA.
Michael
M
Kauffman
Karyopharm Therapeutics Inc, Newton, MA, USA.
Sharon
S
Shacham
Department of Oncology, Wayne State University, USA.
Divaya
D
Bhutani
Department of Oncology, Wayne State University, USA.
Jeffrey
J
Zonder
Department of Oncology, Wayne State University, USA.
Asfar S
AS
Azmi
Department of Oncology, Wayne State University, USA. Electronic address: mohammar@karmanos.org.
Ramzi M
RM
Mohammad
D000178:Acrylamides / Q000494:pharmacology; D021581:Active Transport, Cell Nucleus / Q000187:drug effects*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003520:Cyclophosphamide / Q000494:pharmacology; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D000068338:Everolimus / Q000494:pharmacology*; D006801:Humans; D006834:Hydrazines / Q000494:pharmacology*; D028884:Karyopherins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D008228:Lymphoma, Non-Hodgkin / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology; D008813:Mice, Inbred ICR; D016513:Mice, SCID; D010069:Oxadiazoles / Q000494:pharmacology; D011241:Prednisone / Q000494:pharmacology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D018160:Receptors, Cytoplasmic and Nuclear / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013844:Thiazoles / Q000494:pharmacology; D013997:Time Factors; D051996:Transcription Factor RelA / Q000037:antagonists & inhibitors / Q000378:metabolism; D014230:Triazoles / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects; D014750:Vincristine / Q000494:pharmacology; D023041:Xenograft Model Antitumor Assays; D000097606:Exportin 1 Protein
D000178:Acrylamides; D003520:Cyclophosphamide; D003907:Dexamethasone; D004317:Doxorubicin; D000068338:Everolimus; D006834:Hydrazines; D028884:Karyopherins; D010069:Oxadiazoles; D011241:Prednisone; D047428:Protein Kinase Inhibitors; D018160:Receptors, Cytoplasmic and Nuclear; D058570:TOR Serine-Threonine Kinases; D013844:Thiazoles; D051996:Transcription Factor RelA; D014230:Triazoles; D014750:Vincristine; D000097606:Exportin 1 Protein; C000603655:KPT-251; C586831:KPT-276; C498143:RELA protein, human; C585161:selinexor; C546842:MTOR protein, human
CRM1; Exportin-1; NHL; SINE; Selective inhibitors of nuclear export; XPO1
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