The research program of Martin E. Fernandez-Zapico, M.D., focuses on the cellular and molecular characterization of epigenetic pathways regulating pancreatic carcinogenesis, a dismal disease with one of the poorest prognoses among all neoplasms. Specifically, Dr. Fernandez-Zapico and his team study the modulation of chromatin and nuclear dynamics by oncogenic cascades and its impact in gene expression regulation, a critical step during pancreatic neoplastic transformation.
Dr. Fernandez-Zapico and his team are confident that the knowledge derived from his studies will help with the understanding of the contribution of these epigenetic events to the initiation and/or progression of pancreatic carcinogenesis as well as serve as a foundation for the development of new therapeutic approaches.
Dr. Fernandez-Zapico's program is affiliated with the Mayo Clinic Comprehensive Cancer Center, Department of Oncology, Division of Gastroenterology and Hepatology, and the Center for Cell Signaling in Gastroenterology. His research is supported by the National Institutes of Health (NIH), the NIH-funded Mayo Clinic Pancreatic Cancer Specialized Program of Research Excellence (SPORE), the NIH-funded Mayo Clinic Center for Cell Signaling in Gastroenterology, and the Leukemia and Lymphoma Foundation.
Mechanisms underlying signaling regulation of oncogenic transcription factors. Transcription factors are proteins that regulate gene expression by modulating the synthesis of messenger RNA. Since this process is often one dominant epigenetic control point in the production of many proteins, transcription factors represent the key regulators of numerous cellular functions, including proliferation, differentiation and apoptosis. Pancreatic cancer progression is characterized by activation of a defined profile of transcription factors, including GLIs, NFATs, STATs, CREB and others, that fine-tune gene expression patterns, contributing to the growth and maintenance of these tumors.
However, the signaling controlling the activity of pancreatic oncogenic transcription factors and the epigenetic events associated with the function of these molecules are still poorly understood. Thus, Dr. Fernandez-Zapico's studies have been and continue to be aimed at defining networks activated in pancreatic cancer cells regulating the function of downstream transcription factor complexes participating in pancreatic tumorigenesis.
Epigenetic regulation of the tumor microenvironment. The development of pancreatic cancer results from the dysregulation of cell proliferation and death pathways. In recent years, attention has turned to the desmoplastic reaction, a dominant feature of the active tumor microenvironment present in most pancreatic cancers. This reaction is characterized by an abundant collagen-rich extracellular matrix deposition that influences the growth and survival of pancreatic cancer cells.
Numerous studies have demonstrated that stromal cells (fibroblast and stellate cells) are the primary source for collagen in desmoplasia, and modulate the genesis and maintenance of the desmoplastic reaction in pancreatic cancer; however, the molecular mechanisms by which these cells contribute to the formation of this component of the active microenvironment are still unknown.
Dr. Fernandez-Zapico's group has identified a set of chromatin remodelers such as histone acetyltransferases (p300 and PCAF) and methyltransferases (MLL) in pancreatic cancer stromal cells that can act as regulators of collagen deposition and expression of cytokines involved in stromal cell activation. Currently, his group is furthering its understanding of these complexes in terms of their role as regulators of the tumoral and stromal compartments interaction, which may prove to be crucial to the development of targeted and more successful therapies in the future.
Significance to patient care
Pancreatic cancer is a devastating malignancy for which there is an urgent need for new treatments. Surgical resection is the only curative modality, but a mere 10 percent of patients are candidates for resection — and even then, the five-year survival rate after a curative resection is only 20 percent. In addition, these aggressive neoplasms are highly resistant to conventional chemotherapy.
In fact, Gemcitabine or FOLFIRINOX, the current first-line chemotherapeutic agents for patients with metastatic pancreatic cancer, have only modest survival benefits, and tumor response is rarely achieved. Therefore, the need to develop novel therapies in pancreatic cancer is of paramount importance. The appropriate choice of therapies must be derived from a detailed knowledge of the network controlling the pancreatic transformed phenotype.
Dr. Fernandez-Zapico's research group had identified a novel molecular interaction between the Hedgehog and EGFR oncogenic pathways in pancreatic cancer that uses a GLI1-regulated epigenetic complex as shared effector molecule to modulate cell growth in these tumors. These findings have served as foundation for the development of an ongoing phase I clinical trial in pancreatic cancer targeting these cascades using the available Hedgehog and EGFR inhibitors.