Bessi Qorri
Queen’s University, Kingston, Canada
Title: Novel multi modal targeted therapy for the treatment of pancreatic cancer
Biography
Biography: Bessi Qorri
Abstract
Pancreatic cancer is the only malignancy with a 5year survival rate still in the single digits. The poor prognosis is attributed to the advent of metastatic disease that renders surgery, the only curative option, possible in less than 25% of patients at the time of diagnosis. As a result, the golden standard remains to be palliative chemotherapy, such as gemcitabine. However, patients invariably develop resistance and succumb to disease progression. Thus, there is an urgent need for a therapy that targets the multimodal components contributing to tumorigenesis while sensitizing cells to the cytotoxic effects of chemotherapy. We have previously reported on the role of mammalian lysosomal enzyme neuraminidase-1 (Neu-1) that regulates the activity of several receptor tyrosine kinases (RTKs) including the epidermal growth factor receptor (EGFR). Neu-1 cleaves terminal a-2, 3 sialic acid residues on the ectodomain of the receptor to relieve steric hindrance and allow for receptor dimerization and downstream signaling following ligand binding. Anti-viral oseltamivir phosphate (OP) acts as a structural analog to the a-2, 3 sialic acid, inhibiting Neu-1 activity and ultimately shutting down signaling that is implicated in multistage tumorigenesis. To enhance the efficacy of treatment, anti-diabetic metformin and non-steroidal anti-inflammatory drug acetylsalicylic acid (aspirin) were added to the drug cocktail due to their recently reported chemoprotective roles. Sialidase assays on live aspirin treated, EGF-stimulated PANC-1 pancreatic cancer cells have demonstrated a novel action of aspirin on Neu-1 activity. Immunocytochemistry on PANC-1 cells has revealed that each drug alone alters expression of markers of epithelial-to-mesenchymal transition (EMT) that is characteristic of metastatic cancer, suggesting that they act to prevent EMT and prevent metastasis. Collectively, this multimodal therapy works synergistically to sensitize pancreatic cancer cells to chemotherapy, prevent metastasis, angiogenesis and tumor growth.