Investigation of approaches for overcoming chemoresistance in pancreatic cancer
Hung, Sau Wai
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Pancreatic cancer continues to be one of the most devastating malignances with a 5-year patient survival rate of less than 6%. One of the main reasons for therapeutic failure in patients is the development of resistance towards chemotherapeutic treatment, in particular, gemcitabine. In order to identify novel approaches for overcoming chemoresistance in pancreatic cancer, we focused on targeting three distinct tumor subpopulations that are highly implicated in conferring cancer drug resistance: 1) innately drug-resistant (DR)-phenotype cells, 2) cancer stem cells (CSCs), and 3) epithelial-mesenchymal transition (EMT)-phenotype cells. Enhanced expression of nucleoside transporters (NTs), necessary for gemcitabine uptake into cells, significantly increased gemcitabine efficacy in DR-phenotype cells. This was achieved directly via gene transfer as well as indirectly through the expression of a cell adhesion protein called E-cadherin. Expression of E-cadherin increased the expression, activity, and stabilization of hENT1, allowing for greater drug uptake and efficacy. Similarly, expression of hCNT1 with another transmembrane protein, Cx32, was found to increase gemcitabine accumulation within a heterogeneous tumor cell population. With hCNT1 transporting the drug into cells and Cx32 transferring the drug between cells, the so-called bystander cytotoxic effect could be enhanced. Using a novel epigenetic (i.e., histone methylation) reversal agent, DZNep, we reduced stemness in pancreatic cancer, sensitizing the resistant cancer cell population to gemcitabine without compromising for toxicity in normal pancreatic cells. After drug optimizations, we synthesized novel nanoparticle formulations to deliver the epigenetic-chemotherapeutic combination while mimicking the best dose and schedule. Lastly, we investigated the role of a novel oncoprotein, SET, in conferring EMT and chemoresistance. SET isoform 2 expression promoted EMT through cadherin switching (i.e., from E-cadherin to N-cadherin) via the Rac1/JNK/c-Jun/AP-1 and SPARC/Slug pathways. Overexpression of SET and cadherin switching were also observed in human pancreatic ductal adenocarcinoma tissues. In an orthotopic mouse model of human pancreatic cancer, SET isoform 2 expression facilitated metastasis whereas SET knockdown reduced metastatic tumor burden. These investigational approaches have vital therapeutic implications and may lead to the successful development of new therapeutic strategies for enhancing treatment efficacy in patients.