Feature

Winning the Cancer War

"Hitting angiogenesis is more complicated than we had all originally thought," says Slamon, who has had very good early results testing anti- VEGF in combination with Herceptin. "Because as it turns out, of course, the pathway isn't one growth factor and one growth-factor receptor. We should've figured that out sooner. There's a redundancy in nature, so it isn't quite as simple as shutting off one thing. But the number is finite."

That the signal pathway for angiogenesis is more complex than originally believed creates difficulties, but it also creates opportunities. In fact, it is one of the key reasons the process is a focal point for trying to exploit the stunning potential of the new biology. "Because there are so many steps and so many stages involved in angiogenesis there are also lots of potential targets and strategies," says Dr. David Lyden at Sloan-Kettering.

Lyden and his partner, Dr. Robert Benezra, are in the midst of what might be called the second generation of angiogenesis research. By deleting two genes that play a crucial role in blood-vessel formation, they have produced cancer-resistant mice. That is to say, when they injected some 20 million cancer cells into mice that are bred without the genes, the mice either did not develop tumors or, when they did, they didn't metastasize.

In 1990, in the course of a research project in which he was looking for a molecule that specifically regulated red-blood-cell development, Benezra got lucky. "I not only found a gene that regulated that process but one that seemed, to our delight and amazement, to regulate many different processes that occur during early development. It was one of those rare finds you can get when you're looking for one thing and you end up finding something 100 times more interesting."

Tests on the two related genes confirmed Benezra's observation that they blocked the process required to make mature cells. In the embryonic stage, cells go from being uncommitted, or immature, to maturity, or having a specific function; this is called differentiation. Since these two genes were involved in preventing the process, he labeled them Id1 and Id3 -- inhibitors of differentiation.

"The day when we can do away with chemo is not too far off," says Slamon.

When the two copies of each gene were deleted in the embryonic stage, in work done by Benezra's colleague Dr. Alison Young, brain cells in the mice, as expected, differentiated too early, and the mice bled to death. But the surprise was the defect they saw in the formation of blood vessels. "It turned out that Id1 and Id3 were a requirement for blood-vessel formation, too. This was completely unsuspected in our previous work, so it was really another serendipitous finding, and it's what led us to tumor analysis," says Benezra. (To keep the mice from bleeding to death in future experiments, only three of the four genes were deleted.)

What is particularly significant about the finding is that the two genes appear to play a role in only the developmental stage. After that, they're expressed in very low levels -- except in the blood vessels of tumors. "This is the type of marker," says Lyden, "that people have been looking for for a long time, and there's plenty of interest from big pharma." Sloan-Kettering has entered into an exclusive arrangement with Angiogenex to develop a drug, and although tests in humans are still at least eighteen months away, compounds to suppress the two genes are already in the pipeline.

"Now that we know this gene is required for tumors to grow," says Benezra, "there are factors both upstream -- that turn it on -- and downstream that we can try to hit. This is a gold mine for targets. Not just for us, but for others as well."

Contrast this focused attack, what the scientists refer to as the rational approach, to the way it used to be done. "The National Cancer Institute had a famous screening program that produced many of the drugs currently used to battle cancer," says Slamon. "The way it worked was they'd take these compounds and put them on fifteen or twenty cell lines in a petri dish. Then they asked one simple question: Did it kill cells? And if it did, how many?"

The next step was to put the chemicals into animal models to measure toxicity. And even if there was significant toxicity, the baseline measurement remained the same: Would it kill more abnormal cells than normal ones? "Don't forget, what's considered the modern era of chemotherapy began during World War I with the use of nitrogen mustard gas," says Slamon. "The soldiers who survived the trauma of exposure to the gas lost the lining of their gastrointestinal tract, their bone marrow, and their hair. It screws up the DNA so badly that it can't replicate. And from this came chemotherapy, then the NCI screening program, and we've been doing it pretty much the same way for the last 45 years. Until now."

All of this is still so new -- the sophisticated science, the dazzling technology, the smart research -- that there is still resistance to embracing it in some quarters of the medical community. A fact that Slamon is less and less willing to abide. "There's a whole cadre of physicians, and, even worse, some of the leadership, that are steeped in the traditional approaches," he says. "There are thought leaders who should be at the forefront leading the charge, but they seem more interested in exploiting what they already know as opposed to looking at what they don't. We still have people playing this shell game with chemotherapy drugs -- Well, drug A didn't work, and drug B didn't work, either, but if we try them together and add drug C, maybe that'll work. And they're still touting this kind of thing as a breakthrough. But movement towards the new approaches is taking place, even though sometimes it's like pulling teeth, and the day when we can do away with chemo is not too far off."

But as hopeful as Bert Vogelstein of Johns Hopkins is about where the revolution in understanding cancer will lead, he says it's still too early to make dramatic predictions. He believes that where science is right now in its battle against cancer is analogous to the moment when the polio virus was discovered. "It took three decades to get from the discovery of the polio virus to us being able to do something about polio. And cancer is a group of diseases that are individually much more complex than polio. So it's going to take some time," Vogelstein says. "I can't tell you what will end cancer or what will dramatically reduce the number of deaths, but my gut feeling is it won't be any form of treatment. My money is on prevention. We still can't cure polio. If somebody gets polio, they're as bad off today as they were 100 years ago. But polio is no longer a problem."

At Sloan-Kettering, Dr. Paul Chapman has been working on a vaccine for more than ten years that is being tested in patients with either melanoma or small-cell lung cancer. Though the vaccine has had some good early clinical results, particularly against small-cell lung cancer, the future, he believes, lies in more targeted, gene-based therapies. "Three years ago no one would have ever considered using DNA to vaccinate people," says Chapman. "But that's where a lot of the effort's going now. Traditional vaccines are proteins that have to be purified in the lab and then injected into the body to get an immune response. Now, by injecting DNA instead you can provide the cells with instructions on how to make the proteins themselves."

Like Vogelstein, the National Cancer Institute's Lance Liotta believes that understanding how genes and proteins work will lead to management of the disease and prevention long before there's an actual cure. "We're learning how to block the signal pathways, but that's not necessarily going to kill the cancer cells. They might then be in a dormant state, so you treat for the long term with low-toxicity inhibitors," he says.

Liotta says the the first stage will be treating cancer as a chronic, manageable disease, much like diabetes or high blood pressure. The second stage will be to understand and affect what happens at the premalignant stage of cancer. There are microscopic lesions in the tissue that precede actual development of the disease. "We have micro-dissected these lesions in the lab, and we're analyzing the protein pathways to develop inhibitors to block growth," says Liotta. "And it looks very promising. Since these move much more slowly than advanced, metastatic cancer, you have time to make a difference. And even if we were able to double the time it takes for them to progress to malignancy, that would be beyond the normal life span of the patient anyway."

To the degree that the scientists are willing to talk in actual months and years at all, there is something of a consensus, at least on the general picture. "Six months from now," says Slamon, "treatments will not be all that much different except for a few updates. Three years from now, there'll be an explosion of the new, targeted therapies in clinical use. And in six years, there'll be whole new systems, drugs, and approaches."

And until that time, medical science has one crucial prescription: Hold on.