Asfar S Azmi, Yosef Landesman, Erkan Baloglu, Amro Aboukameel, Irfana Muqbil, Michael Kauffman, Philip A Philip, Sharon Shacham, Ramzi M Mohammad
Pancreatic cancer remains a deadly disease in urgent need of newer therapeutic modalities. Pancreatic tumors are very heterogeneous and carry alterations in many critical pathways (i.e. harboring a robust biological network) rendering the design of therapy against a single pathway unrealistic. The disease requires a broad form of therapy that can target the activation of multiple tumor suppressor proteins simultaneously. It has been consistently shown in pancreatic cancer biopsies that there is an over-expression of the nuclear exporter protein exportin 1 also known as Chromosome maintenance region 1. Nuclear exporter protein exportin 1 is recognized to export major nuclear residing tumor suppressor proteins causing their functional inactivation through their mislocalization to the cytoplasmic compartment. This makes exportin 1 an attractive therapeutic target in pancreatic cancer. Supporting this we have clearly demonstrated that targeted inhibition of exportin 1 by our specific inhibitors of nuclear export can restore the function of multiple tumor suppressor proteins leading the pancreatic cancer cell death and tumor inhibition in orthotopic models. Additionally, studies have demonstrated that specific inhibitors of nuclear export synergize with gemcitabine and nab-paclitaxel leading to enhanced pancreatic cancer growth inhibition, apoptosis, and disintegration of cancer stem cell mimicking spheroids. Collectively these studies have lead to a Phase Ib/II clinical evaluation of specific inhibitors of nuclear export with GEM and nab-paclitaxel in patients with metastatic pancreatic cancer (ClinicalTrials.gov Identifier: NCT02178436). In this mini-review we highlight the promising specific inhibitors of nuclear export in pancreatic cancer.
