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 manipulate 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 selectively replicate 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.
© 2012 Salk Institute for Biological Studies
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