Preclinical assessment with clinical validation of selinexor with gemcitabine and nab-paclitaxel for the treatment of pancreatic ductal adenocarcinoma

Asfar S. Azmi, Husain Yar Khan, Irfana Muqbil, Amro Aboukameel, Jasper E. Neggers, Dirk Daelemans, Amit Mahipal, Gregory Dyson, Mandana Kamgar, Mohammad Najeeb Al-Hallak, Anteneh Tesfaye, Steve Kim, Vinod Shidham, Ramzi M. Mohammad, Philip A. Philip

Research output: Contribution to journalArticle

2 Scopus citations

Abstract

Purpose: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease urgently requiring new treatments. Overexpression of the protein transporter exportin-1 (XPO1) leads to mislocalization of tumor-suppressor proteins (TSP) 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 antitumor activity of multiple TSPs leading to suppression of PDAC in vitro and in orthotopic models. Experimental Design: We evaluate the synergy between SINE compounds and standard-of-care treatments in preclinical models and in a PDAC Phase Ib trial. Results: 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) subcutaneous xenografts. 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 (1,000 mg/m2 i.v.) and nab-paclitaxel (125 mg/m2 i.v.) on days 1, 8, and 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. Conclusions: Our preclinical and ongoing clinical study lends support to the use of selinexor-GEM-nab-paclitaxel as an effective therapy for metastatic PDAC.

Original languageEnglish (US)
Pages (from-to)1338-1348
Number of pages11
JournalClinical Cancer Research
Volume26
Issue number6
DOIs
StatePublished - Mar 15 2020

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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    Azmi, A. S., Khan, H. Y., Muqbil, I., Aboukameel, A., Neggers, J. E., Daelemans, D., Mahipal, A., Dyson, G., Kamgar, M., Al-Hallak, M. N., Tesfaye, A., Kim, S., Shidham, V., Mohammad, R. M., & Philip, P. A. (2020). Preclinical assessment with clinical validation of selinexor with gemcitabine and nab-paclitaxel for the treatment of pancreatic ductal adenocarcinoma. Clinical Cancer Research, 26(6), 1338-1348. https://doi.org/10.1158/1078-0432.CCR-19-1728