The 30 Year Quest To Tame The ‘Wily’ Cancer Gene

Michael Robertson was on his summer vacation a few years ago and had just proposed to the woman who would become his wife when he decided he needed to see a doctor.

“I’d been having symptoms for a few months but it was during an intense work period, drinking too much coffee, not getting enough sleep, so I kind of chalked it up to that,” Robertson says. Unfortunately, the doctor had a more dire diagnosis: stage 4 rectal cancer.

Robertson was only 35 at the time — unusually young for this diagnosis. His treatment involved chemotherapy, radiation, surgery and two experimental treatments. Those have kept him alive for six years, but his cancer has not been stopped.

One challenge is that Roberson’s tumor is driven by a very common mutation and there’s no drug that can target that mutation directly.

The mutated gene is called RAS, and it’s the very first human cancer gene ever discovered. It’s also amazingly common – found in 30 percent of all cancers and responsible for a million cancer deaths worldwide, every year.

The word RAS didn’t mean much to Robertson at the time, “It was just another acronym — another medical term,” he says. His doctor “explained it’s common. It’s a tough one to treat.”

But RAS is currently in the center of a fast-moving medical research drama.

“It’s a major player in lung cancer and the major driver of pancreatic cancer and also a major player in colon cancer and many other cancers as well,” says Frank McCormick at the University of California, San Francisco.

McCormick knows all about RAS. He was working at Cetus, a small biotech company in the Bay Area, back in the early 1980s when this cancer gene was identified. He convinced his company to look for drugs and tests to combat it.

“We took off from there, got into the game and made a few early discoveries and I fell in love with the project,” McCormick says. And he’s been dogging this key part of cancer ever since.

The healthy RAS gene instructs the cell to make a protein that is basically an on/off switch that tells living cells when to start dividing. “But in cancer cells, the switch is basically defective so it’s stuck in the on state most of the time,” says McCormick.

With cell division jammed in the on position, the cells proliferate and create tumors. Given the gene’s central role in cancer, many drug companies jumped in to try and develop drugs to fix this broken switch.

“People got into the drug discovery game very early for RAS,” he says. “They tried and failed very early also, so people moved away from RAS as a target.”

Other cancer genes proved to be much easier to attack with drugs.

“It got the moniker ‘undruggable’ because we’ve been working on it for 35 years and so far we don’t have a drug in the clinic that works,” says Adrienne Cox, a cancer biologist at the University of North Carolina Lineberger Comprehensive Cancer Center.

Like McCormick, she has also spent her entire career working on RAS. She says the failure to come up with a drug is not for lack of trying.

“It’s because RAS is a wily beast,” she says. “It’s been described variously as a greasy ball, meaning there’s no good pocket to stick a drug into.”

That’s how other targeted cancer drugs work — they jam up the works and kill the cancer cells. But drug companies couldn’t find a drug that would stick to this greasy ball. Then, about four years ago, the then-head of the National Cancer Institute, Harold Varmus, decided to focus on RAS.

“This started when Harold said, ‘Guys, this is embarrassing. We don’t have a drug,’ ” Cox recalls. ” ‘What’s the problem here?’ ”

Varmus dedicated about $10 million a year for a coordinated effort to find drugs that will work against RAS. Cox is part of that effort, and so is Frank McCormick. In fact, McCormick leads the effort, which is run out of the NCI’s Frederick National Laboratory in Maryland.

Inside a drab industrial-park building, about 60 people work together to home in on RAS. They have determined the exact shape of the RAS protein. They’ve studied how it binds to the inside of cancer cells, using microscopes that can pick out single molecules. And they’ve been checking out hundreds of thousands of chemical compounds to see what could possibly be turned into a drug.

One idea is to find compounds that will prevent this protein from binding to the inside of the cell, where it must lodge in order to function. That strategy doesn’t require a drug to stick to the greasy ball.

“Right now I’d say that’s top of the list because we’re actually making progress in that area,” McCormick says.

And the RAS Initiative, as it’s known, is far from the only effort taking a fresh interest in this critical cancer gene.

In fact, some of the most intriguing leads are developing elsewhere. Kevan Shokat, a Howard Hughes Medical Institute investigator and colleague of McCormick’s at UCSF, identified a particular mutant of RAS that has a weak spot (the Star Wars Death Star comes to mind) where drugs can bind. This mutant (called KRAS G12C) is common in lung-cancer tumors.

Several pharmaceutical companies are now trying to develop drugs to latch onto that spot, including Wellspring Biosciences in San Diego. Shokat and McCormick have financial ties to that company.

The first targeted drugs could be tested in people later this year, McCormick says. Michael Robertson, the colorectal cancer patient, remains hopeful that he will be eligible to participate in a clinical trial that targets his RAS mutation.

“The general public shouldn’t go out and call their stockbrokers and think it’s all over,” Cox says, “but for those of us in the field for a long time, these are real advances.”

For Cox, it comes after 30 years of painfully slow progress, “so to see a real glimmer of light at the end of the tunnel is pretty rewarding.”

McCormick says he doesn’t see any reason why this won’t be cracked in the next few years. “I’m sure it will be.”

But he adds, “They won’t be simple, one-off drugs that cure cancer forever.” Unfortunately, cancers eventually develop resistance to these kinds of targeted drugs, so they may help for a matter of months, or occasionally for a period of years, but they are rarely cures.

I asked McCormick if his decades-long quest to conquer RAS was akin to Captain Ahab’s obsessive quest for the great white whale, Moby Dick.

“Not yet!” he replied with a laugh. But remember how Herman Melville’s novel ended: Ahab ultimately tracked down the white whale, but Moby Dick prevailed in the end.

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