Clodagh O'Shea
e-mail: oshea@salk.edu |
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Clodagh O’Shea, an assistant professor in the Molecular and Cell Biology Laboratory, is employing the help of a small DNA virus, called adenovirus, to both understand and treat cancer. Normally, cellular replication is tightly controlled. However, both DNA viruses and tumor cells sabotage such controls to drive their respective pathological propagation, albeit with one small difference: In tumor cells the key cellular players are targeted via mutations, while in infected cells viral proteins achieve the same end. Not surprisingly, many of the cellular targets are the same. Dr. O’Shea's lab is exploiting this overlap to help address three key questions:
What are the critical cellular targets and pathways that drive deregulated growth?
Human tumors acquire a myriad of mutations, which makes it difficult to pinpoint the critical therapeutic targets. In contrast, adenovirus encodes a relatively small number of proteins that overcome all the cellular checkpoints which normally prevent aberrant replication. Hence, uncovering the cellular targets of these viral proteins is a powerful strategy with which to identify key cellular pathways that may also be deregulated in tumorigenesis. In addition, viral proteins can provide novel insights into how such targets could be modulated for cancer therapy. Dr. O’Shea’s lab is currently using this paradigm to gain new insights into the p53 tumor suppressor pathway, PI-3 Kinase/mTOR signaling and RNA export/processing in tumorigenesis.
What is the human growth deregulation program and how do we uncouple it for tumor therapy?
Tumor mutations act together within integrated and complex cellular networks to elicit aberrant replication. Unfortunately, the overlapping and interconnected nature of cellular networks implies that therapies which target any single tumor mutation are likely to be ineffective. But how do we determine the correct combinations of therapeutic targets that will uncouple a pleiotropic human growth deregulation program? Just as viral proteins can be used to identify discrete tumor targets, Dr. O’Shea’s lab is exploring whether viral infection can be exploited to reveal the overall program for human growth deregulation. Using a systems biology approach, they are determining the key molecular signatures that are common to both infected primary cells and tumor cells. With the help of viral mutants, RNAi and chemical genetics, this is also a powerful experimental platform in which to test and identify combination therapies that selectively abort aberrant replication, but leave normal cells unharmed.
Can we engineer viruses as novel therapeutic agents that trigger the rapid lytic death of tumor cells but leave normal cells unharmed?
The overlap between the tumor and viral growth deregulation programs can also be exploited to develop viruses that replicate selectively in tumor cells, killing them from the inside. This approach is called oncolytic viral therapy, something that is of particular interest to Dr. O’Shea. Defective viruses that are unable to inactivate critical normal cell checkpoints replicate selectively in tumor cells in which these checkpoints are inactivated by mutations. Defining how tumor cells complement selectively the replication of defective viruses can also reveal unexpected tumor targets, such as altered tumor RNA export as the therapeutic target of ONYX-015. Oncolytic viruses offer a novel and potentially self-perpetuating cancer therapy: Each time a virus homes in on a cancer cell and successfully replicates, the virus ultimately kills the cancer cell by bursting it open to release thousands of viral progenies, which have the potential to seek out remaining tumor cells and distant micro-metastases.
Ringshausen, I., O'Shea, C.C., Finch, A.J., Brown Swigart, L., and Evan, G.I. (2006). Mdm2 is critically and continuously required to suppress lethal p53 activity in vivo. Cancer Cell 10(6), 501-514.
O'Shea, C.C. (2005). Viruses: tools for tumor target discovery and agents for lytic cancer therapies- an introduction. Oncogene 24, 7636-7639.
O'Shea, C.C. (2005). Viruses- seeking and destroying the tumor program. Oncogene 24, 7640-7655.
O'Shea, C. C., Soria, C., Bagus, B., and McCormick, F. (2005). Heat shock phenocopies E1B-55K late functions and selectively sensitizes refractory tumor cells to ONYX-015 oncolytic viral therapy. Cancer Cell 8(1), 61-74. (Cover Article).
O'Shea, C. C., Choi, S., McCormick, F., and Stokoe, D. (2005). Adenovirus overrides cellular checkpoints for protein translation. Cell Cycle 4(7), 883-888.
O'Shea, C. C., Klupsch, K., Choi, S., Bagus, B., Soria, C., Shen, J., McCormick, F., and Stokoe, D. (2005).Adenoviral proteins mimic nutrient/growth signals to activate the mTOR pathway for viral replication. Embo Journal 24, 1211-1221.
O'Shea, C. C., and Fried, M. (2005). Modulation of the ARF-p53 pathway by the small DNA tumor viruses. Cell Cycle 4(3), 449-452.
O'Shea, C. C. (2005). DNA tumor viruses - the spies who lyse us. Current Opinion in Genetics and Development 15, 18-26.
O'Shea, C. C., Johnson, L., Bagus, B., Choi, S., Nicholas, C., Shen, A., Boyle, L., Pandey, K., Soria, C., Kunich, J., Shen, Y., Habets, G., Ginzinger, D., McCormick, F. (2004). Late viral RNA export, rather than p53 inactivation, determines ONYX-015 tumor selectivity. Cancer Cell 6, 611-623.
Clodagh O’Shea received her PhD. from the University of London where she was a Bursar at the Imperial Cancer Research Fund London Research Institute. Her postdoctoral studies took her to the Comprehensive Cancer Center at the University of California in San Francisco, where she was a Human Frontiers in Science Program Fellow and Leukemia Society of America Fellow.
