Abstract

Pancreatic Cancer: Genetic models to develop novel diagnostic and therapeutic strategies. Pancreatic ductal adenocarcinoma (PDAC) is a fatal disease with poor patient outcomes often resulting from late diagnosis in advanced stages. To improve prognosis, novel diagnostic and therapeutic strategies are urgently needed. Using various genetic PDAC models, my lab investigates the role of different signal transduction pathways during tumour initiation, progression and metastasis and translates this knowledge into novel strategies for early endoscopic detection and treatment of the disease. To identify druggable Kras downstream signalling pathways, we performed genetic gain and loss of function studies in mice. We show that cell autonomous PI3K /Akt signalling is an essential downstream effector of oncogenic Kras in the pancreas. Targeting the PI3K pathway in established genetically engineered PDAC shows strong antiproliferative effects. These data strongly indicate that PI3K is a promising targetable node for pancreatic cancer prevention and therapy. In order to investigate cell autonomous and non-cell autonomous signalling pathways mediating progression, maintenance and therapeutic resistance of PDAC in vivo, we have generated mouse models for sequential and host specific gene (in)activation by combining the Flp/frt with the Cre/loxP recombination system. As a proof of principle, we activated a latent diphtheria toxin A allele in established PDAC and observed profound tumour regression within a few days.