Abstract 3476: Evaluable antitumor activity in metastatic pancreatic adenocarcinoma with specific inhibitor of nuclear export based treatment
Authors: Asfar S. Azmi, Yosef Landesman, Michael Kauffman, Sharon Shacham, Gabriel Mpilla, Amro Aboukameel, Steve Kim, Mandana Kamgar, Anteneh Tesfaye, Ramzi M. Mohammad, Philip A. Philip
Journal: Cancer Research (2019)

Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) remains a deadly disease in urgent need of newer therapeutic modalities. Earlier we have shown that in PDAC, the over-expression of the nuclear exporter protein Exportin-1 (XPO1) leads to functional inactivation of tumor suppressor proteins (TSPs; FOXO3a, p27, Par-4 etc.) through mis-localization. We demonstrated that inhibition of XPO1 by CRISPR/Cas9 validated Selective Inhibitor of Nuclear Export (SINE) Selinexor and analogs restores the anti-tumor function of multiple TSPs leading to PDAC cell death and tumor inhibition in orthotopic models. Methods: Here we evaluate the synergy between SINE compounds and standard of care gemcitabine-nab-paclitaxel in PDAC models in vitro, in vivo and in a Phase Ib/2 trial (NCT02178436). Results: Selinexor and second generation SINE compound eltanexor synergized with gemcitabine (GEM) and nab-paclitaxel leading to suppression of PDAC growth, induction of apoptosis, and superior spheroid disintegration of PDAC derived cancer stem cells (CSCs). The observed synergy was due in part to enhanced nuclear localization of TSPs and suppression of both CSCs and epithelial-to-mesenchymal transition (EMT) markers. Label-Free quantitative (LFQ) proteome profiling with nuclear and cytoplasmic enrichment showed superior enhancement in nuclear protein fraction in combination treatment. The protein class with highest percent of nuclear retention were DNA binders. Selinexor and eltanexor as single agent (used at MTD) inhibited the growth of PDAC-CSC and two patient derived (Pdx) sub-cutaneous xenografts (p&amp;lt;0.01). In combination experiment, selinexor-GEM-nab-paclitaxel used at sub-MTD dose could significantly suppress the growth of PDx tumors. Molecularly, we observed down-regulation of CRM1 and target TSPs ex vivo. In a Phase 1b/2 study examining patients with metastatic pancreatic cancer, 9 patients were exposed to selinexor (60 mg oral) with GEM (1000 mg/m2 IV) and nab-paclitaxel (125 mg/m2 IV) once weekly (Mondays) for 3 weeks. Evaluable responses were observed in patients on this trial. 2 patients showed partial response (PR) and 2 had stable disease. Outstanding objective response was observed in 1 patient who demonstrated remission for 16 months and remained alive for 22 months. Remarkable and sustained reduction in CA19-9 levels were observed in the responding patient. Conclusions: These results rationally fortify selinexor-gemcitabine-nab-paclitaxel as new and effective therapy for metastatic PDAC and strengthen our ongoing Phase II study. Citation Format: Asfar S. Azmi, Yosef Landesman, Michael Kauffman, Sharon Shacham, Gabriel Mpilla, Amro Aboukameel, Steve Kim, Mandana Kamgar, Anteneh Tesfaye, Ramzi M. Mohammad, Philip A. Philip. Evaluable antitumor activity in metastatic pancreatic adenocarcinoma with specific inhibitor of nuclear export based treatment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 3476.