Azmi, Khan, Muqbil, Aboukameel, Neggers, Daelemans, Mahipal, Dyson, Kamgar, Al Hallak, Tesfaye, Kim, Shidham, Ramzi, Philip (2019) Preclinical assessment with clinical validation of Selinexor with gemcitabine and nab-paclitaxel for the treatment of pancreatic ductal adenocarcinoma Clinical cancer research : an official journal of the American Association for Cancer Research ()

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Over-expression of the protein transporter exportin-1 (XPO1) leads to mislocalization of tumor suppressor proteins (TSPs) and their inactivation. Earlier, we showed that blocking XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) compounds (selinexor and analogs) restores the anti-tumor activity of multiple TSPs leading to suppression of PDAC in vitro and in orthotopic models. We evaluate the synergy between SINE compounds and standard of care treatments in pre-clinical models and in a PDAC Phase Ib trial. SINE compounds synergize with gemcitabine (GEM) and nanoparticle albumin-bound (nab)-paclitaxel leading to suppression of PDAC cellular growth and cancer stem cell (CSC) spheroids disintegration. Label-Free quantitative proteome profiling with nuclear and cytoplasmic enrichment showed superior enhancement in nuclear protein fraction in combination treatment. Selinexor inhibited the growth of PDAC CSC and two patient derived (PDX) sub-cutaneous xenograft. Selinexor-GEM-nab-paclitaxel blocked PDX and orthotopic tumor growth. In a Phase 1b study (NCT02178436), 9 patients were exposed to selinexor (60 mg oral) with GEM (1000 mg/m2 IV) and nab-paclitaxel (125 mg/m2 IV) on day 1, 8, 15 of 28-day cycle. Two patients showed partial response and 2 had stable disease. An outstanding, durable objective response was observed in one of the responders with progression free survival of 16 months and overall survival of 22 months. Our pre-clinical and ongoing clinical study lend support to the use of selinexor-gemcitabine-nab-paclitaxel as an effective therapy for metastatic PDAC. Copyright ©2019, American Association for Cancer Research.

Links

http://www.ncbi.nlm.nih.gov/pubmed/31831564
http://dx.doi.org/10.1158/1078-0432.CCR-19-1728

Tools