SF Gate

10-2-00

THE BODY’S OWN CANCER DEFENSE

UCSF researcher publishes possible solution to mysterious failure of protective proteins

Tom Abate, Chronicle Staff Writer

Monday, October 2, 2000

Frank McCormick grew excited as he sketched out the solution to a cancer mystery that he and fellow researchers at the University of California at San Francisco may have finally cracked.

"The black box is gone," said McCormick, director of UCSF’s Comprehensive Cancer Center. "We can see what is wrong in cancer cells, what cancer cells do to survive and how they can be vulnerable to treatment."

This black box has dogged McCormick, casting a shadow upon an otherwise promising approach to cancer that he has pursued for eight years, first at a Bay Area biotechnology company and now at one of the world’s most prestigious research centers.

His possible solution to the mystery— the explanation is laid out in the current issue of the journal Nature Medicine— could have broad consequences, because it identifies new targets for cancer drugs.

At the center of the mystery is a gene called p53, one of the most important factors in preventing or permitting cancers to grow.

It was discovered by Arnold Levine, who today is president of Rockefeller University in New York City. Subsequent research showed that the p53 gene makes a protein of the same name which plays a key role in curbing cancer.

"P53 can detect when cells are dividing abnormally," said Karen Vousden, an investigator with the National Cancer Institute in Frederick, Md. "It kills the cell to save the organism."

But scientists think roughly half of all cancers spread because the p53 gene is missing or deactivated in the cells where cancer originates.

So McCormick, while he was chief scientist at Onyx Pharmaceuticals in Richmond, came up with an idea for turning this p53 defect into a cancer-fighting tool.

By the late 1980s, other researchers had shown that certain microbes—like certain cancer cells—somehow dodge or deactivate p53. This allows the virus to take over the cell and use it, like a factory, to make more copies of itself without interference from p53. If it were active, p53 would detect the illicit replication and kill the cell.

In 1987, a graduate student in the lab of Arnold Berk, a microbiologist at the University of California at Los Angeles, designed a mutant version of the common cold virus that seemed to lack the ability to shut down p53. In this advance, McCormick saw the germ of an idea for turning this mutant "adenovirus" into a cancer-fighting weapon.

McCormick theorized that if Onyx could introduce the mutant adenovirus into a cancer cell that lacked a p53 defense, the virus would take over. It would keep reproducing copies of itself until the cell literally exploded from the inside out—like putting too much water into a balloon.

Moreover, McCormick reasoned, such a strategy might also be safe and selective. If the mutant virus escaped the cancer region and tried to invade normal cells, it would be no big deal because the cell’s p53 defense would simply shut the virus down—and the mutant had no way to stop p53.

McCormick created a sensation when he published this theory in 1996 in the prestigious journal Science. Onyx has subsequently made this mutant virus into a drug, Onyx- 015, and begun testing it on patients with head and neck tumors, in the hopes of one day winning government approval to sell it as a remedy.

Onxy stock shot up in August after the company announced positive results of a Phase II clinical trial, in which the drug was given to small numbers of patients to make sure it is safe. The company is beginning Phase III trials to determine its effectiveness.

McCormick, who left the company and joined UCSF in 1997, found that while the drug seemed to work on head and neck cancers, his premise seemed to have some problems. Other scientists found that the mutant adenovirus grew in some cancer cells that seemed to have intact p53 defense systems.

"The premise of Onyx-015 was that the virus would only grow in cells where p53 was inactive," said McCormick. His paper in the current Nature Medicine proposes a solution to that mystery, while shedding more light on the body’s anti- cancer defenses.

It turns out p53 goes into action only when it gets a signal from a series of other chemicals, beginning with the protein E2F. When a cell begins to divide abnormally, the E2F protein becomes overactivated. This overactivity sends a signal to a protein called P14ARF.

Like falling dominoes, P14ARF triggers a change in the protein MDM2 which, in turn, regulates p53.

In the body’s normal state, MDM2 plays the essential role of suppressing the activity of p53, said Vousden, the cancer institute researcher. Without MDM2, p53 would run amok and kill normally dividing cells—and ultimately the entire body.

"The critical thing is to keep p53 under control," she said. Only when an upsurge of E2F signals the growth of a cancer is P14ARF dispatched to break down MDM2, thus freeing p53 to kill the cancer cell, she said.

What McCormick shows in his Nature Medicine paper is that some cancer cells lack P14ARF. As a result, when E2F signals excessive growth, there’s no chemical messenger to tell MDM2 to get off p53, so p53 can kill the cancer cell.

"It’s like somebody snipped the alarm wire," McCormick said. Thus some cancers may have the p53 gene, and may appear to have working p53 defense. But the cancerous cell may have a defective or missing copy of P14ARF, so MDM2 never gets the order to let p53 swing into action. "This explains the controversy that has been clouding Onyx- 015," McCormick said.

Tyler Jacks, a cancer specialist at the Massachusetts Institute of Technology in Cambridge, said the new understanding about the chain of events in the p53 pathway has important ramifications for cancer treatment.

McCormick, meanwhile, believes UCSF’s cancer center will continue to contribute its share of basic understandings that will help expose more of the peculiarities and differences between the various types of cancer—and showing eventually how to attack each type of cancer in turn.

"Given where we are now, and what we already know we can do to improve

current experimental therapies, I think we’ll begin to tick off cancers one at a

time," he said. "It’s going to happen one by one, and not in the too distant future."