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Retooling the Common Cold Virus to Target Cancer Cells?


The tiny adenovirus protein known as ORF3 (shown in green) clears the way for adenovirus replication by creating "zip files" of genes that help the cell defend itself against the virus. O'Shea hopes to exploit this finding to create adenoviruses that selectively destroy cancer cells.

A novel mechanism that adenovirus uses to sidestep the cell's suicide program could go a long way toward explaining how tumor suppressor genes are silenced in tumor cells and pave the way for a new type of targeted cancer therapy, according to a study published by Clodagh O'Shea in the journal Nature.

When a cell is under stress, the tumor suppressor p53 springs into action, activating an army of foot soldiers that initiate a built-in "autodestruct" mechanism to eliminate virusinfected or otherwise abnormal cells from the body. Not surprisingly, the p53 tumor suppressor pathway is inactivated in almost every human cancer, allowing cancer cells to escape normal growth control mechanisms. Yet there is still no rationally designed targeted cancer therapy to treat patients based on the loss of p53.

"All of the targeted therapies we have are based on small molecules that inactivate oncogenes, but cancer is not solely caused by the gain of growth-promoting genes," says O'Shea, an assistant professor in the Molecular and Cellular Biology Laboratory. "The loss of tumor suppressors is just as important. The big question is how do you target something that's no longer there?"

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Listen to Clodagh O'Shea as she talks about her research. Click here>>

Adenovirus seemed to provide the answer. It brings along a viral protein that binds and degrades p53 in infected cells. But if deprived of the protein, adenovirus should only be able to replicate in p53-deficient tumor cells. Then, each time it bursts open the host cell to release thousands of viral progeny, the next generation of viruses is ready to seek out remaining cancer cells while leaving normal cells unharmed. "This makes adenovirus a perfect candidate for oncolytic cancer therapy," says O'Shea.

Yet to everybody's surprise, patient responses did not correlate with the p53 status of their tumors. Intrigued, she and her team followed up on this unexpected finding. They quickly realized that the protein was only half of the story.

It turned out that adenovirus brings along another protein, which neutralizes the p53 checkpoint through a completely different mechanism. Instead of inactivating p53 directly, the tiny protein modifies chromatin, the dense histone/DNA complex that keeps everything neatly organized within the cell's nucleus. These modifications cause parts of chromosomes to condense and bury the regulatory regions of p53 target genes deep within. With access denied, p53 is powerless to pull the trigger on apoptosis.