Aberrant Gene Expression: Diagnostic Markers and Therapeutic Targets for Pancreatic Cancer

Jeran Kent Stratford: Aberrant gene expression: diagnostic markers and therapeutic targets for pancreatic cancer (Under the direction of Jen Jen Yeh and Channing J. Der) Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer and the fourth leading cause of cancer-related death in the United States. The overall median survival for patients diagnosed with PDAC is five to eight months. The poor outcome is due, in part, to a lack of disease-specific symptoms that can be used for early detection, and as such, most patients present with locally advanced or metastatic disease at the time of diagnosis. Therefore, the need for diagnostic tools is both great and urgent. Furthermore, current chemotherapies have low response rates and high toxicity, limiting their use, and there are currently no effective targeted therapies for PDAC. Therefore, a greater understanding of the underlying biology of pancreatic cancer is needed to identify tumor-specific vulnerabilities that can be therapeutically exploited. Pancreatic cancer development is driven by genomic changes that alter gene expression. Aberrant gene expression produces changes in protein expression, which in turn may confer growth advantages to the tumor; often the tumor then develops a dependency on continued aberrant gene and protein expression. Determining how aberrant genome-wide gene expression changes affect the biology of the tumor is of paramount importance in our continued efforts to improve patient therapy. By identifying and establishing a role for the overexpressed genes in PDAC we can discover new avenues for therapeutic intervention and iv potentially predict the most effective therapy for each individual and avoid therapies that may have little clinical efficacy. My research aimed to identify aberrantly expressed genes in primary tumor samples from PDAC patients and characterize the diagnostic and therapeutic value of the identified genes. The work outlined in this dissertation focuses first on identifying a prognostic signature of genes with the ability to stratify patients into high and low risk groups, and second on assessing the biological importance of overexpression of the dual-specificity protein kinase TTK for pancreatic cancer oncogenesis. Together these two investigations provide a basis for translating molecular changes in tumor biology into improved therapy for pancreatic cancer patients. v To Mindy, my ever steady companion vi ACKNOWLEDGEMENTS First I wish to thank my mentors, Jen Jen Yeh and Channing Der. I sincerely thank you for all of the encouragement and time you have spent on my behalf as advisors. It was only through your …