Developmental signaling pathways involved in pancreatic adenocarcinoma
A primary focus of our research program explores the prognostic and therapeutic implications of aberrant developmental signaling in pancreatic cancer. While it is established that canonical Wnt signaling is required for pancreatic cancer initiation and progression, less is understood about how variations in pathway activation dictate differences in prognosis and treatment response. We have demonstrated the importance of Wnt ligand-mediated signaling as critical determinant of pathway activation and response to Wnt-targeting agents, including porcupine inhibitors, vitamin D and other small molecules.
Factors contributing to KRAS-initiated pancreatic cancer progression
While the role of oncogenic KRAS mutation as a pivotal mediator of pancreatic cancer initiation and progression is well accepted, the importance of various other molecular alterations or environmental factors in promoting tumor progression are less well understood. We have worked extensively with both cell lines and the versatile transgenic model of pancreas-specific oncogenic Kras expression (KC mouse) to evaluate the role of several genetic and environmental factors in accelerating dysplastic progression to pancreatic cancer.
Epigenetic events in cancer progression
Global alterations in DNA methylation and post-translational histone modifications are cancer hallmarks that are frequently linked to corresponding changes in gene expression and genomic instability. We have demonstrated how cellular histone modification levels and DNA methylation events can serve as prognostic or predictive biomarkers in pancreatic cancer and continue to explore their causal relationships to cancer progression and therapeutic resistance.
Global molecular profiling of pancreatic cancer
Pancreatic adenocarcinomas share a small number of high frequency driver mutations in an otherwise far more highly heterogeneous landscape of other genetic and epigenetic alterations. This diversity contributes to variable patient outcomes and response to therapy. Making use of primary patient samples and various unbiased approaches (i.e., microarrays, high throughput sequencing, mass spectrometry), we have collaborated with various investigators to identify genetic, epigenetic and proteomic events linked to disease-specific survival. These studies have revealed multiple molecular alterations and signaling pathways linked to clinical aggressiveness. These studies further offer potential therapeutic targets and biomarkers for predicting survival and treatment response
Improving clinical management of pancreaticobiliary neoplasms
We have collaborated extensively with clinical colleagues to determine the potential value of various clinicopathologic factors and novel biomarkers in the clinical management of pancreaticobiliary neoplasms, including pancreatic cysts, pancreatic neuroendocrine tumors and adenocarcinomas of the pancreas, bile duct and ampulla. Leveraging a large clinical database and biospecimen repository at UCLA, we have examined established guidelines for surgical decision-making, determined the efficacy of neoadjuvant chemotherapy in locally advanced pancreatic cancer, and explored the prognostic and predictive utility of several putative biomarkers.