All ETDs from UAB

Advisory Committee Chair

Martin Johnson

Advisory Committee Members

Donald Buchsbaum

Andra Frost

Michael Ruppert

Jeffrey Smith

Document Type


Date of Award


Degree Name by School

Doctor of Philosophy (PhD) Heersink School of Medicine


Pancreatic adenocarcinoma (PAC) is the fourth leading cause of cancer mortality in the United States. Despite the use of highly aggressive treatment regimens (surgery, chemotherapy and radiation), almost all patients succumb to metastatic disease within 6-10 months of diagnosis. The hedgehog (HH) signaling pathway was originally discov-ered to play a critical role in mammalian embryological development. Interestingly, re-cent studies have suggested that aberrant expression of this pathway is involved in the initiation and continued growth of PAC. Small molecules that antagonize the transmem-brane protein Smoothened (Smo), a critical signaling component of the HH pathway, have proven effective in decreasing PAC growth both in vitro and in vivo and show promise as a new therapeutic strategy. Data from our laboratory indicate the HH path-way is overexpressed in pancreatic cancers and Smo antagonism decreases pancreatic cancer cell growth in vitro. The major accomplishments of this dissertation research in-clude (1) the validation of a recently developed technique known as Taqman low-density array (TLDA) which can be used to analyze the expression of multiple genes in a single RNA sample, (2) the identification of novel, tumor-associated genes through an extensive characterization of the HH pathway and its transcriptional targets in PAC clinical speci-mens (both surgically resected tissues and fine-needle biopsies) and (3) the identification of genes associated with in vitro response to cyclopamine, a selective HH pathway inhibi-tor, in human pancreatic cancer cell lines. These findings contribute to the growing char- iii acterization of the HH pathway in pancreatic cancer etiology and may provide a basis for future clinical applications in which PAC patients most likely to respond to HH pathway antagonists could be identified based upon gene expression profiling, thereby maximizing the efficacy of this type of therapy.



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