Alexandra Demcsak M.D., Ph.D.

Overview

Aim: Early Detection

Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic malignancy with high mortality rate due to the lack of efficacious diagnostic, preventive and therapeutic options. The main reasons for the poor survival rate are that diagnosis is often made at an advanced stage, PDAC shows great resistance against chemotherapeutic and radiotherapy regimens and only a handful of patients are eligible for surgical intervention. Therefore, there is an imminent need to better understand how PDAC is initiated and to develop novel diagnostic and screening tools. Since advanced stage PDAC is difficult to treat, identification of tumor precursors and risk factors represents a better strategy for prevention and to achieve prolonged survival rates. Although there have been important advances in the elucidation of molecular mechanisms that lead to PDAC development, the role of inborn genetic mutations that increase PDAC risk are incompletely understood, yet provide preventive strategic options.

The role of digestive enzymes in the development of pancreatic cancer is poorly understood. Recent studies suggested that reduced levels of the digestive enzyme chymotrypsin due to genetic mutations increase the risk for pancreatic cancer. Recently, deletion variant in chymotrypsin B2 (CTRB2) that results in loss of chymotrypsin function was reported as a risk factor for PDAC. In this proposal, we will investigate whether altered chymotrypsin expression accelerates PDAC initiation in a novel mouse model. The results of our study will offer better understanding on how chymotrypsin deficiency alters PDAC development, and provide information on genetic risk factors of PDAC in order to facilitate better screening of patients at risk. Our hope is to inform future clinical trials testing the protective effect of chymotrypsin against pancreatic cancer development.