Research in Genetic Roots of Cancer Paying Off in New Therapies
Twenty years of research into the origins of malignancy crystallize into one profound insight: Cancer is a disease of genes gone bad.
This idea has revolutionized the way scientists look at cancer, and it seems certain to change the way doctors treat it too. Many believe medicine is on the brink of an entirely new approach to controlling this most feared of diseases, one that targets the genetic flubs at the heart of cancer and reverses them.
In hindsight, the biggest cancer news of modern times is so very simple. All tumors spring from typos in the assembly plans for proteins that tell cells when to grow and when to die.
Like many big ideas, the discovery of cancer’s roots dawned gradually. One experiment at a time, seemingly irrelevant bits of scientific fact mass into a new way of thinking.
Among these was an almost-forgotten experiment at Massachusetts Institute of Technology in 1981. A team led by molecular biologist Robert Weinberg explored whether some genetic element inside tumor cells could transform normal ones into cancer.
One day the scientists pulled the DNA out of a kind of rat cancer called a neuroblastoma and put the genes into mouse cells. Soon healthy cells became cancerous.
The seed turned out to be a flawed bit of genetic code, one of the first discoveries in a new class known as oncogenes. The scientists called it “neu” and moved on. They had no idea that what they found would ever be relevant in treating breast cancer, a disease that kills 43,500 women yearly.
But in the completely unpredictable way that basic discoveries morph into truly useful information, Weinberg’s rat gene became key. It is at the heart of the first effective human cancer treatment based on exploiting the genetic differences between cancer cells and healthy ones.
Herceptin, the medicine that grew out of that MIT experiment, is moving toward U.S. Food and Drug Administration approval for breast cancer and could be on the market this fall.
“The translation of this basic research into the clinic is just beginning,” says Weinberg, now a researcher at the Whitehead Institute for Biomedical Research in Cambridge. “We are seeing the harbinger of what is going to happen in the next decade of the new century.”
If treatments work as well as many expect, they will destroy malignant cells but leave healthy ones alone, sparing patients the frightful side effects of standard cancer therapy.
“Everyone in the field is excited because this black box called cancer is not such a mystery anymore,” says Dr. Bert Vogelstein of Johns Hopkins University, another of the field’s early explorers. “Once you understand something, medical history shows it’s only a matter of time before you can exploit that and do something about it.”
That matter of time, though, can be considerable. Several years passed after Weinberg’s discovery before other scientists found a human counterpart of neu, a gene they called HER-2/neu. The gene produces a protein on the surface of cells that serves as a receiving point for growth-stimulating hormones.
Dr. Dennis Slamon’s team at UCLA found that about 30% of women with breast cancer have many extra copies of this gene. The result: Their breast cells reproduce out of control and spread through their bodies.
Scientists reasoned that they might reduce HER-2/neu’s impact by somehow blocking the extra hormone docking points created by the gene. At Genentech Inc., they cloned antibodies designed to do this. One turned out to be Herceptin, which eventually proved able to shrink and sometimes even eliminate widely spread breast cancer.
The National Cancer Institute estimates that at least 10 to 20 drugs now in human testing are designed, like Herceptin, to stop cancer by fixing bad genes.
What’s broken in cancer are the genes that rule the cell’s life cycle. Each gene contains the building plan for a protein, including ones that trigger the cell to divide and eventually die in an orderly way.
When one of these normal genes develops a disastrous glitch, it’s called an oncogene. An oncogene may stay turned on, constantly pouring out growth-promoting protein that ordinarily occurs only in brief bursts. Or it may produce a protein that is overly powerful.
When all goes well, another class of genes, called tumor-suppressor genes, detects these mistakes and orders the cell to either fix the foul-up or die. When the suppressor gene itself is broken, however, cancer moves another step closer.
Generally it takes several different genetic flaws, accumulated over a lifetime, to tip a cell into uncontrolled growth. Even when that happens, however, another decade or two may pass before it grows into a tumor large enough to be noticed.
Dr. Stephen Friend of Fred Hutchinson Cancer Research Center in Seattle, a co-discoverer of tumor-suppressor genes, notes that only this year have researchers begun to feel confident about the potential of genetic approaches to cancer.
“You can bet we will have a significant effect on curing cancer,” he predicts. “It’s now no longer a question. It’s just which approach will prove out.”
Many experts doubt that any of the drugs now in human testing will be a slam-dunk cure for cancer--or for any of the 100-plus individual diseases that are called cancer. Like Herceptin, which adds three months to the lives of terminally ill breast cancer patients, these medicines may help some people sometimes, but they are likely to be used mostly in combination with standard chemotherapy, radiation and surgery.
All major pharmaceutical firms, plus many small biotech companies, are working on genetic approaches to cancer. Among the targets farthest along:
* Ras. This normal growth-signaling gene becomes an oncogene when it mutates and sticks forever in the “on” position, delivering an erroneous order to divide again and again. It’s often involved in colon, lung and pancreatic cancer.
Researchers are testing drugs that interfere with farnesyl transferase, an enzyme that helps carry out one step in a chemical chain reaction that delivers the ras gene’s growth signal.
* EGF receptor. Short for epidermal growth factor, this spot on the surface of cells receives growth signals secreted by other organs. It relays the message inside the cell to the ras gene, which takes it the next step.
In some cancers, cells have many extra copies of the EGF receptor, so the growth message gets vastly amplified. Researchers are testing antibodies, similar to Herceptin, that block the EGF receptor.
* P53. This is one of more than 50 known tumor-suppressor genes. About half of tumors escape the body’s anti-cancer surveillance system, in part because of bad p53 genes.
Several teams are experimenting with treatments that introduce good copies of p53 into tumors, where they oversee their destruction. Another approach is targeting cells with a virus that kills those without a working p53 gene.
“This is just the very beginning,” says Dr. Jack Roth of M.D. Anderson Cancer Center in Houston, who is testing p53-based treatments.
Friend, who pioneered the field of suppressor genes, notes that the pipeline between a basic discovery and the development of a useful drug can be up to 10 years. Therapies based on attacking oncogenes are farther along in the pipeline because oncogenes were discovered first, not because they are necessarily the best target.
“The excitement is not because the first drops are out of the faucet,” Friend says. “It’s because the pipeline is full now of great ideas.”
The next generation of genetically based cancer drugs is likely to be built on more recent discoveries in the subtle differences that set cancer apart. Among these are insights into the regulation of mitosis, the way cells divide; apoptosis, the process that makes cells die on schedule, and telomerase, an enzyme that cancer uses to short-circuit the cell’s built-in limit on the number of times it can divide.
Since 1980, the National Cancer Institute has spent more than $13 billion for scientists like Weinberg to study the basic biology of cancer. Weinberg is deeply pleased to see the start of a payoff with the advent of Herceptin.
“It’s the first time in my life that anything I’ve done has had any favorable effect on anybody’s health,” he says. “I feel very good about it.”
