美国国家公共电台 NPR The 30-Year Quest To Tame The 'Wily' Cancer Gene

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 2 mutation 3 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 4, 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 5: RAS is the very first human cancer gene 1 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 6 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 7. 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 8 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 9 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 10 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 11 about $10 million a year for a coordinated 12 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 14 onto the membrane 15 where it needs to be in order to work. McCormick says that's a promising 16 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 17.

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 13 onto, a mutant found commonly in lung cancer. Pharmaceutical 18 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 19 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 20 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 21. 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 22 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.

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