The Radiation Potential: Emerging strategies in pancreatic cancer treatment

Pancreatic ductal adenocarcinoma (PDAC) has a poor prognosis, as reflected by its low 5-year overall survival rate. Current treatment remains limited to surgical resection of the tumor and/or chemotherapy. Although chemotherapy enhances the effect of radiation, radiotherapy is currently only used to manage pain in PDAC, owing to controversial results from various studies. Therefore, identifying opportunities for radiation to be implemented as therapeutic option are needed. Thus, this thesis aimed to study the role of radiation, providing an overview of different strategies to enhance the efficacy of radiation, while addressing the challenges of the tumor microenvironment of PDAC and emerging therapy resistance in different preclinical models. Chapter 2 underscores the importance of excessive growth of the stroma, which could hamper the effects of chemotherapy. In Chapter 3, we incorporated a component of the stroma through the addition of pancreatic stellate cells to PDAC cells to form 3D spheroid models, and studied the role of inhibitors targeting the c-MET receptor. In Chapter 4, we highlighted the potential of a triple combination targeting c-MET and its ligand, hepatocyte growth factor, and gemcitabine, serving as a potential treatment line. Chapter 5 provides a comprehensive overview of the tumor-grafted chick chorioallantoic membrane (CAM) as an alternative cancer research model as well as upstream and downstream applications for further research. Chapter 6 discusses the efficacy of nanocarrier-mediated radiosensitizers and the delivery-related obstacles. In Chapter 7, the efficacy of encapsulated ultrasmall gold nanoparticles and a cisplatin prodrug in combination with radiation were assessed. Chapter 8 describes the proteomic analysis of irradiated PDAC cell lines to experimentally simulate therapy resistance. In Chapter 9 molecular mechanisms were investigated between gemcitabine- and paclitaxel-resistant PDAC cell lines. Lastly, Chapter 10 describes the radiobiological aspects of ultra-high dose rate radiation technique FLASH.