The subject of this dissertation is novel therapeutics for pancreatic cancer treatment, with a special focus on evaluating experimental in vitro treatment options illustrated in Figure 2. This dissertation consists of three parts, (1) Pancreatic ductal adenocarcinoma; for which Chapter 3 describes the genetic features of pancreatic cancer that have an effect on treatment response. Chapter 4 then indicates how proteomic analysis of gemcitabine resistant cells reveals the contribution of microtubule-associated protein 2 (MAP2) to taxane treatment. Chapter 5 is a review on how to assess in vitro combination treatments by mathematical approaches to predict synergism, antagonism or additive effects. In the final chapter of Part 1, Chapter 6, the role of c-Met inhibitors, alone and in combination with gemcitabine, in primary co-cultures of human pancreatic cancer and stellate cells, are described to overcome drug resistance. Part (2) highlights the role of cancer metabolism as a novel therapeutic strategy. Chapter 7, summarizes the role of the glycolytic pathway and connects it to cancer metastasis. Chapter 8 describes the lactate dehydrogenase inhibitor NHI-Glc-2 and its potential in cancer treatment. In addition, this part covers the essential cellular process of ribosome biogenesis in cancer. In particular, Chapter 9 summarizes the ribosome biogenesis and explores the role of ribosomal RNA methyltransferase Fibrillarin as potential therapeutic target. In Chapter 10, it is shown that CX-5461, a RNA polymerase I inhibitor and G-quadruplex stabilizer, inhibits pancreatic cancer cell growth and cell migration and induces DNA damage. Part (3) describes the novel antimetabolite fluorocyclopentenylcytosine, RX-3117, as summarized in Chapter 11. The activation enzyme of RX-3117, uridine cytidine kinase 2 (UCK2), is evaluated as a potential biomarker of pancreatic cancer in Chapter 12. The RX-3117 mediated downregulated of DNA methyltransferase 1 (DNMT1) that leads to the reexpression of tumor suppressor genes and proton coupled folate carrier 1 (PCFT-1) is described in Chapter 13. Lastly, Chapter 14 describes molecular mechanisms of resistance to RX-3117.
|Qualification||Doctor of Philosophy|
|Award date||31 May 2021|
|Place of Publication||Amsterdam|
|Publication status||Published - 1 Jun 2021|