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Calculus and Cancer Drug Development Studies Stephan Gysin, PhD UCSF Helen Diller Family Comprehensive Cancer Center The Problem: Human Pancreatic Cancer Challenge of the 21st century 4th 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 The pancreas is a gland: Exocrine: releasing digestive enzymes into the duodenum Endocrine: injecting hormones into the blood (e. g. insulin) Pancreatic Ductal Epithelial Cells Model: Pancreatic cancer develops in a multistep process normal pancreatic duct PanIN-1A PanIN-1B PanIN-2 PanIN-3 Distinct stages of pancreatic cancer development The end product is an aggressive cancer. adenocarcinoma taken from R. Hruban at Johns Hopkins 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. Clusters of pancreatic cancer cells Pancreatic cancer cell lines in culture Highly metastatic variants Metastatic variants show different phenotype Normal Cells Oncogenes Tumor Suppressors Cancer Cells Signaling Proliferation Migration/Invasion Survival Angiogenesis