Developmental Research Program Abstracts
The Developmental Research Program supports several ongoing research projects. These projects currently include:
- Prostate-Specific Membrane Antigen (PSMA) in Hepatocellular Carcinoma
- Detection of Malignancy in Biliary Brushings Using Genomic Markers: A Phase 1 Study
- Determining the Role of PTEN/AKT Signaling in Extrahepatic Cholangiocarcinoma Using a Novel Genetic Mouse Model
Prostate-Specific Membrane Antigen (PSMA) in Hepatocellular Carcinoma
The principal investigators of this project are David A. Woodrum, M.D., Ph.D., and Scott M. Thompson, M.D., Ph.D., both in the Department of Radiology at Mayo Clinic in Rochester, Minnesota.
Current molecular imaging strategies to diagnose and monitor liver cancer are not very effective. There's a vital need to identify new molecular targets to more effectively diagnose and treat liver cancer. This research project should provide important information that can be used to translate new liver cancer imaging and therapies to patients.
Detection of Malignancy in Biliary Brushings Using Genomic Markers: A Phase 1 Study
The principal investigator of this project is Vinay Chandrasekhara, M.D., a gastroenterologist at Mayo Clinic's campus in Rochester, Minnesota.
Biliary malignancies, in particular cholangiocarcinoma (CCA), are associated with poor prognosis and limited treatment options. Therefore, early diagnosis is critical for maximizing treatment outcomes.
Identification of these malignancies is complicated by diagnostic challenges, including differentiation of benign from malignant biliary strictures by imaging, sample failure of conventional cytologic brushings, and well-differentiated tumor cells that mimic reactive inflammatory nonmalignant processes. The sensitivity of conventional brush cytology during endoscopic retrograde cholangiopancreatography (ERCP) is as low as 8% for the detection of cholangiocarcinoma.
Members of our investigational team first described the use of fluorescence in situ hybridization (FISH) to improve the sensitivity for the detection of malignancy in bile duct brushing specimens compared with standard cytology. We then demonstrated that a refined optimized set of FISH probes further increased diagnostic sensitivity. While FISH improves the diagnostic sensitivity for CCA, it is a time-intensive test requiring expertise and manual review that results in increased cost, longer turnaround time and lack of widespread adoption. Thus, brush cytology remains the diagnostic standard at most centers around the world despite its suboptimal performance characteristics.
Genomic testing is now playing a large role in the diagnosis, risk-stratification and choice of therapy for a variety of malignancies. Genomic testing is comparatively easier to perform compared with FISH and widely available, therefore making it an attractive option for the diagnosis of biliary malignancy. In addition, genomic testing can be performed as a standard assay that doesn't require manual review or skilled trained laboratory staff for analysis, thereby allowing for easier test interpretation and dissemination.
The purpose of this phase 1 study is to identify a set of genomic markers with the potential to improve the detection of malignancy in a prospectively collected biliary brush sample discovery cohort. A future prospective validation cohort would require expansion of this effort into a potential program in the Hepatobiliary SPORE.
Determining the Role of PTEN/AKT Signaling in Extrahepatic Cholangiocarcinoma Using a Novel Genetic Mouse Model
The principal investigator for this project is Baoan Ji, M.D., Ph.D., a cancer biology researcher at Mayo Clinic in Jacksonville, Florida.
Cholangiocarcinoma is an aggressive cancer that forms in the cells that line the bile duct. The five-year survival rate is less than 10%, and the only treatment options for patients include aggressive chemotherapy, radiation or surgery. Cholangiocarcinoma can start either from the cells that line the bile duct within the liver (intrahepatic) or outside the liver (extrahepatic). Extrahepatic CCA accounts for more than 90% of all cholangiocarcinoma cases.
To date, there hasn't been a mouse model to study the disease. In this proposal, we have two major goals: 1) Creating a genetic mouse model for studying extrahepatic CCA; 2) Studying how the PTEN-AKT signaling pathway affects the progression of inflammation to cancer in CCA.
An abnormal increase in PI3K/AKT signaling is observed in more than 80% of cholangiocarcinoma cases in humans. PTEN negatively regulates the PI3K/AKT pathway. Therefore, PTEN deletion results in constant activation of the PI3K/AKT pathway.
We were recently able to delete the PTEN gene in mouse bile duct cells. In these PTEN-deleted mice, enlargement of the extrahepatic bile duct developed as early as one month after birth. Microscopically, we were able to see inflammation, fibrosis, ductal cell proliferation and precancerous lesions. The phenomenon mimics what is seen in human chronic cholangitis, which is a risk factor for cholangiocarcinoma.
In contrast to the obvious phenotype seen in the bile duct, PTEN deletion in the pancreatic duct did not lead to disease. We reasoned that bile salt stimulation is involved in extrahepatic CCA. This new genetic mouse model will help us test our central hypothesis that bile salts activate the PTEN-AKT signaling pathway in bile duct cells to initiate a disease spectrum from cholangitis to CCA. In Specific Aim 1, we are studying the roles of the PTEN-AKT pathway in disease development from inflammation through neoplasia during extrahepatic cholangiocarcinoma formation. In Specific Aim 2, we are testing whether bile salts trigger cell proliferation, inflammation and fibrosis through the PTEN-AKT signaling pathway.
This study is crucial because a cholangiocarcinoma mouse model will help us understand how this disease develops in humans and will allow us to test new therapies.