1. Calculus and Cancer Drug Development Studies Stephan Gysin, PhD UCSF Helen Diller Family Comprehensive Cancer Center

2. The Problem: Human Pancreatic Cancer  Challenge of the 21 st century  4 th leading cause of cancer deaths  33’000 people with pancreatic cancer die each year in the USA  Cancer is usually detected late during progression  Patients often refractory to any surgical treatment  Radiation and chemotherapy often not very rewarding  Markers/tools for early detection are missing

3. Pancreatic Ductal Epithelial Cells The pancreas is a gland: Exocrine: releasing digestive enzymes into the duodenum Endocrine: injecting hormones into the blood (e. g. insulin)

4. normal pancreatic duct PanIN-1APanIN-1BPanIN-2PanIN-3 adenocarcinoma Model: Pancreatic cancer develops in a multistep process The end product is an aggressive cancer. taken from R. Hruban at Johns Hopkins Distinct stages of pancreatic cancer development

5. Properties of cancer cells:  Capacity to divide continuously  Bypass pathways that lead to cell death  Attract and trigger the formation of blood vessels (angiogenesis)  Capacity to migrate and invade different organs (metastasis) The driving force for these properties are mutations that accumulate over time. Cancer cells are genomically instable, i. e. they constantly acquire mutations that allow them to adopt mechanisms for uncontrolled growth.  Oncogenes: Genes that when mutated drive and accelerate cancer progression  Tumor suppressors: Genes that stop or slow down cancer progression; cancer cells acquire mutations in tumor suppressors that functionally inactivate them.

6. Clusters of pancreatic cancer cells Highly metastatic variants Pancreatic cancer cell lines in culture Metastatic variants show different phenotype

7. Normal Cells Cancer Cells Oncogenes Tumor Suppressors Signaling Proliferation Survival Angiogenesis Migration/Invasion