Identification of Specific Genes that Contribute to Pancreatic Cancer Cell Growth
Dr. Billadeau has in the past worked with signaling pathways usually found to be active only in blood cells. However, he recently demonstrated that one such pathway, involving the signal transduction molecule vav1, is present and activated in 50 percent of pancreatic tumors, but not in the normal pancreas. Further experiments have suggested that this pathway contributes to the processes that cause normal pancreatic cells to become cancerous.
In addition, Dr. Billadeau has shown that a separate pathway involving the kinase GSK-3 is also activated in pancreatic cancers. Further experiments have shown how this kinase regulates the expression of molecules that control cell survival and proliferation.
Dr. Billadeau’s findings are exciting because they provide two new potential chemotherapeutic targets against a malignancy that is highly resistant to chemotherapy. He is currently examining the effect of various anti-cancer agents on these two signaling pathways and developing strategies to design new agents specifically targeted at proteins in these pathways. These studies form the basis for a project that is part of the Specialized Programs of Research Excellence (SPORE) grant in pancreatic cancer, recently renewed by the National Cancer Institute to the Mayo Clinic Cancer Center.
Elucidation of Signaling Pathways That Regulate the Response to DNA Damage
In collaboration with Junjie Chen, Ph.D., a former member of this Program, Dr. Lou discovered a protein called the Mediator DNA Damage Checkpoint Protein 1 (MDC-1), which plays a critical role in activation of cellular responses after DNA damage. His subsequent studies have revealed the types of damage that recruit this protein and its role in several distinct DNA damage-activated pathways. His ongoing studies are designed to test the hypothesis that loss of this protein contributes to the development of cancer.
More recently Dr. Lou has demonstrated that Deleted in Breast Cancer Protein 1 (DBC-1), the product of a gene that is frequently lost during the development of breast cancer, serves to regulate activity of the growth and survival promoting protein SirT2. Cells that express diminished DBC-1 as a result of targeted gene deletion or silencing have lost an important negative regulator of growth and exhibit resistance to the induction of apoptosis. In follow-up studies, Dr. Lou’s group is trying to identify the most important cellular changes that result from DBC-1 loss and contribute to breast cancer development.
Identifying Cancer Promoting Changes in Gene Transcription
Many of the changes in cancer cells lead to elevated expression of various genes that would ordinarily be turned off during embryological or postnatal development. Dr. Fernandez-Zapico is studying the causes for this altered gene transcription, focusing primarily on the causes of altered transcription in pancreatic cancer.
In pancreatic cancer two of the best studied alterations lead to increased signaling by the epidermal growth factor receptor (EGFR) and a molecule called Hedgehog. Dr. Fernandez-Zapico’s studies have demonstrated that signaling by EGFR and Hedgehog leads to complementary changes in the same network of proteins that regulate transcription factors, thereby leading to increased expression of genes controlled by that network. Importantly, neither EGFR signaling nor Hedgehog signaling alone is capably of mediating these changes, providing new understanding of how these two cancer causing pathways synergize. Ongoing studies by the Fernandez-Zapico laboratory, funded by the Specialized Programs of Research Excellence (SPORE) grant in pancreatic cancer, are not only designed to increase understanding of cancer promoting changes in this transcription factor network, but also to explore the effects of inhibiting this network using various inhibitors and combinations of inhibitors of the upstream signaling.
Developing the Next Generation of Anti-Cancer Drugs
Members of the Developmental Therapeutics Program are working to identify and study the next generation of chemotherapeutic agents in their laboratories.
Read more about some ongoing projects.
© 2013 Mayo Foundation for Medical Education and Research. All rights reserved.