KIOS-FM

The 30-Year Quest To Tame The 'Wily' Cancer Gene

Mar 9, 2018
Originally published on March 9, 2018 1:38 pm

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.

You can contact Richard Harris at rharris@npr.org.

Copyright 2018 NPR. To see more, visit http://www.npr.org/.

RACHEL MARTIN, HOST:

This next story is about a line of cancer research that could potentially help a huge number of people, people like Michael Robertson.

MICHAEL ROBERTSON: I'd been having unidentified symptoms for a few months, but it was during a intense work period. I was drinking too much coffee, not sleeping enough. And so I kind of chalked it up to that.

MARTIN: But when this 41-year-old man finally made it to the doctor, he was diagnosed with stage 4 colorectal cancer. A genetic mutation called RAS was at the core of his disease.

ROBERTSON: It didn't mean anything to me at the time. It was just - you know, another acronym, another medical term.

MARTIN: It turns out RAS is the driving force in about 30 percent of all cancers, a million cancer deaths each year. And no drug can target this mutation - at least not yet. NPR's Richard Harris picks up the story.

RICHARD HARRIS, BYLINE: RAS is the very first human cancer gene ever discovered. It also turns out to be amazingly common.

FRANK MCCORMICK: 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.

HARRIS: Frank McCormick was working at a small biotech company in the San Francisco Bay Area back in the early 1980s when this cancer gene was identified. And he convinced his company to look for drugs and tests to combat it.

MCCORMICK: We took off from there and sort of got into the game and made a few early discoveries and fell in love with the whole project.

(LAUGHTER)

MCCORMICK: A long time ago.

HARRIS: 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.

MCCORMICK: But in cancer cells, the switch is basically defective. So it's stuck in the on state most of the time.

HARRIS: So cells just keep on dividing and forming tumors. Given the gene's central role in cancer, many drug companies jumped into the fray to develop drugs to fix this broken switch, McCormick says.

MCCORMICK: People got into the drug discovery game very early for RAS. They tried and failed very early also. So (laughter) people moved away from RAS as a target.

ADRIENNE COX: It got the moniker on 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.

HARRIS: Adrienne Cox at the University of North Carolina 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.

COX: It's because RAS is a wily beast. It's been described variously as a greasy ball, meaning there's no good pockets to stick a drug into.

HARRIS: 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.

COX: So this started when Harold said, guys, this is embarrassing. You know, we don't have a drug. What's the problem here?

HARRIS: 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 Cancer Institute labs in Frederick, Md.

Here, about 60 people are working together to home in on RAS.

Dwight Nissley leads me into a room where a robot is busy picking up plastic lab dishes and moving them from one instrument to the next.

DWIGHT NISSLEY: So this laboratory right here is a lab where we do a lot of the screening.

HARRIS: The scientists can screen as many as 100,000 compounds a week looking for potential drugs. One strategy is to find compounds that can stick to this greasy ball. Another idea is to prevent the on/off switch from latching onto the membrane where it needs to be in order to work. McCormick says that's a promising strategy.

MCCORMICK: Well, right now I'd say that's top of the list because we're actually making progress in that area and have some compounds which seem to be at least first step in a process towards doing that.

HARRIS: Some of the most promising ideas are coming from colleagues who are not part of the NCI initiative that McCormick is coordinating.

MCCORMICK: So we are, in the big picture, a small piece of a big effort.

HARRIS: Scientists have found a particular mutant of RAS that drugs can latch onto, a mutant found commonly in lung cancer. Pharmaceutical companies are rushing to develop drugs based on that discovery. For the man with colorectal cancer, Michael Robertson, that day can't come soon enough. But Adrienne Cox says this will take time.

COX: The general public shouldn't go out and call their stockbrokers and think it's all over. But, you know, for those of us in the field for a long time, these are real advances.

HARRIS: And for Cox, it comes after 30 years of painfully slow progress.

COX: And so to see a real glimmer of light at the end of the tunnel is pretty rewarding.

HARRIS: McCormick agrees with her.

MCCORMICK: I don't see any reason whatever to say this is not going to be cracked in the next few years. I'm sure it will be.

HARRIS: Now, these scientists are, by nature, optimists. Otherwise, they wouldn't have kept at this very hard problem for decade upon decade. I asked McCormick if he felt like Captain Ahab obsessively pursuing Moby Dick.

Is this your white whale?

MCCORMICK: (Laughter) Not yet.

(LAUGHTER)

HARRIS: So I guess it is important to remember how that story ends.

MCCORMICK: Exactly.

(LAUGHTER)

HARRIS: Spoiler alert - Captain Ahab tracked down the white whale, but Moby Dick prevailed in the end.

Richard Harris, NPR News.

(SOUNDBITE OF REAL ESTATE'S "SATURDAY") Transcript provided by NPR, Copyright NPR.