Clodagh C. O'Shea, PhD
Salk Institute for Biological Studies (La Jolla, CA)
Next generation oncolytic adenoviruses for p53–selective tumor therapy.
Most chemotherapies in general use are little more than DNA poisons that slow down tumor growth but do not ultimately cure patients. Chemotherapy also has devastating side effects, which is especially tragic in children. There is a desperate need to identify new drugs and therapeutic modalities that conclusively ablate cancer cells but leave normal cells unharmed. The p53 tumor suppressor pathway is inactivated by mutations in almost every cancer and yet we have no targeted drugs to treat p53 defective tumors.
The overall objective of this proposal is to develop viruses that act as p53-mutation guided missiles, which specifically replicate within p53 mutant tumor cells to implode them from the inside-out. Currently there is no new therapy on the horizon that has more potential than such ‘oncolytic viruses.’ To develop these viral cancer therapies, we will exploit the striking similarities that exist between virally infected cells and tumor cells.
Adenovirus is a small DNA virus-little more than a protein coat protecting its genome-that reproduces courtesy of the host cell. Normally, cellular replication is a tightly controlled process. However, both adenoviruses and tumor cells overcome cellular controls to drive their respective limitless propagation. Not surprisingly, tumor cells and adenoviruses subvert many of the same cellular checkpoints, albeit with one small difference: In tumor cells the key cellular players are targeted via mutations, while adenovirus uses viral proteins to achieve the same end. The p53 checkpoint normally ‘guards’ our cells against the pathological replication that occurs in cancer and adenovirus infection. Therefore, both tumor cells and adenovirus must inactivate p53; all tumor cells inactivate p53 by mutations and adenovirus encodes a protein called E1B-55K that destroys p53.
Thus, it was proposed that ONYX-015, a mutant adenovirus that does not have the E1B-55K protein, would only replicate in tumor cells with a mutant p53 checkpoint. However, this turned out to be not so simple, but now we know why. We recently discovered that even when E1B-55K is no longer present, adenovirus has yet another viral protein that inactivates p53 functions. This is an exciting discovery, because with this knowledge we can finally create a virus that has no more options for inactivating p53. This will prevent the virus replicating in normal cells and allow it to only replicate in tumor cells with p53 mutations.
Such a virus would offer a novel and potentially self-perpetuating p53 cancer therapy: Each time a virus homes in on a p53 mutant tumor cell and successfully replicates, the virus ultimately kills the cancer cell by bursting it open to release thousands of viral progenies, which are ready to seek out remaining tumor cells and distant micro-metastases. The goals of this proposal are to develop these next generation p53-tumor selective replicating viruses, which have the potential to help save the lives of many cancer patients.
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Clodagh O’Shea, PhD
Professor, Molecular and Cell Biology Laboratory
Howard Hughes Medical Institute Faculty Scholar
Salk Institute for Biological Studies
10010 N Torrey Pines Rd
La Jolla, CA 92037