Onyx 015 has Broad Application for Treatment of Cancer

UCSF researchers may have discovered why an experimental anticancer drug - a genetically modified version of a cold virus - works more broadly than had been expected.

The finding could solidify and expand use of the drug - Onyx-015 - and reveals a potential new target for therapy that could prompt the development of other cancer drugs.

Onyx-015 was designed to hone in on cancer cells, specifically those in which the p53 tumor-suppressor gene - a key sentinel of cell health - does not function. P53 is mutated and does not function in 60 percent of cancers. The theory has been that, without the p53 defense, Onyx-015 could replicate in cancer cells.

However, researchers have observed in clinical trials and cell culture studies that Onyx-015 also works against tumors in which the p53 tumor-suppressor gene appears to remain intact. This has created heated debate in the scientific community about the drug's efficacy and mechanism of action.

Now, the UCSF researchers believe they have solved the conundrum: In the October issue of Nature Medicine, they report that while some tumors responding to Onyx-015 have mutations in the p53 gene itself, others have a defect in another gene, known as p14 ARF, which is located "upstream" in the p53 pathway and which indirectly regulates p53 function. They showed that loss of p14 ARF leads to the deregulation of another protein, Mdm2, which in turn inhibits p53. As a result, p53 cannot shut down the engineered virus' attempt to take over the cellular machinery, replicate incessantly and eventually kill the cell - action that, counterintuitive as it may be, is just what researchers want to happen when it comes to cancer cells.

The finding "solves a big puzzle about the drug's mechanism of action," says a co-author of the study and the drug's creator, Frank McCormick, PhD, director of the UCSF Comprehensive Cancer Center, and cofounder of Onyx Pharmaceutical Inc., which develops the drug. "Inactivating p14ARF is just another way of turning off p53."

The finding also suggests the possibility of new applications for Onyx-015, says the senior author of the study, Michael Korn, MD, UCSF assistant adjunct professor of medicine. "Our work supports the idea of exploring the use of Onyx-015 in tumors that we presumed would be immune to the drug because they were thought to frequently have p53 genes, such as melanoma and glioblastoma [a form of brain cancer]. Clinical trials have to show if the p14 ARF and p53 status could serve as a reliable predictor of response to treatment with Onyx-015."

The finding could also lead researchers to consider how to design other genetically engineered viruses that take the p14 ARF mechanism into consideration, says Korn.

Moreover, he says, the discovery suggests that p14 ARF could potentially become a therapeutic target in itself. A drug that could reactivate p14 ARF would reactivate p53, thereby reinvigorating the cell's defenses. To date, researchers have focused clinical trials of Onyx-015 on cancer types that previous studies have shown often have inactivated p53, though the drug has been administered randomly. The new findings, says Korn, will encourage the researchers to clarify the status of 53 and p14ARF in the individual tumors targeted.

Onyx-015 is an example of the new wave of cancer therapies emerging based on researchers' growing understanding of the molecular mechanisms of cancer and viruses. Researchers know that p53 plays the crucial role of halting cell division when it detects that a cell's DNA has been damaged, as occurs in cancer or when a virus enters a cell. In many cases, loss of p53 function is one of the first of several steps leading to the disruption of a cell's regulatory processes.