Repositioning of Old Drugs for Novel Cancer Therapies: Continuous Therapeutic Perfusion of Aspirin and Oseltamivir Phosphate with Gemcitabine Treatment Disables Tumor Progression, Chemoresistance, and Metastases

SIMPLE SUMMARY: Repositioning old drugs in combination with clinical standard chemotherapeutics opens a promising clinical treatment approach for patients with pancreatic cancer. This report presents a therapeutic repositioning of continuous perfusion of aspirin and oseltamivir phosphate in combination with gemcitabine treatment as an effective treatment option for pancreatic cancer. The data suggest that repositioning these drugs with continuous perfusion with gemcitabine disables chemoresistance, tumor progression, EMT program, cancer stem cells, and metastases in a preclinical mouse model of human pancreatic cancer. These promising results warrant additional investigation to assess the potential of translating into the clinical setting to improve the cancer patient prognosis for an otherwise fatal disease. ABSTRACT: Metastatic pancreatic cancer has an invariably fatal outcome, with an estimated median progression-free survival of approximately six months employing our best combination chemotherapeutic regimens. Once drug resistance develops, manifested by increased primary tumor size and new and growing metastases, patients often die rapidly from their disease. Emerging evidence indicates that chemotherapy may contribute to the development of drug resistance through the upregulation of epithelial–mesenchymal transition (EMT) pathways and subsequent cancer stem cell (CSC) enrichment. Neuraminidase-1 (Neu-1) regulates the activation of several receptor tyrosine kinases implicated in EMT induction, angiogenesis, and cellular proliferation. Here, continuous therapeutic targeting of Neu-1 using parenteral perfusion of oseltamivir phosphate (OP) and aspirin (ASA) with gemcitabine (GEM) treatment significantly disrupts tumor progression, critical compensatory signaling mechanisms, EMT program, CSC, and metastases in a preclinical mouse model of human pancreatic cancer. ASA- and OP-treated xenotumors significantly inhibited the metastatic potential when transferred into animals.