Winning the Cancer War

On a beautiful winter afternoon in Southern California, Dr. Dennis Slamon, one of the country’s premier cancer researchers, is sitting at a picnic table on the UCLA campus. The grounds are quiet, almost deserted for the New Year’s break, and Slamon seems as relaxed as someone who runs a major research lab, a network of more than 50 patient centers, and two national cancer-research programs can be. Between bites of tuna salad, he is telling me, warmly and authoritatively, how life works. Life, that is, at the molecular level.

I’d come out to Los Angeles to have a conversation with Slamon that I hoped would make sense of the remarkable progress being made on some of the most intractable diseases – particularly cancer – in recent years. Even if you haven’t been paying close attention, you’ve probably noticed that medical news now comes at a fast and furious pace. You’ve probably also noticed it now comes with a heightened if somewhat vague sense of optimism. Every few days bring fresh headlines about revolutionary treatments, newly discovered drugs, or miraculous cancer breakthroughs.

This, despite the fact that the major killers have barely been slowed. More than half a million Americans continue to die every year from cancer, and another million new cases are diagnosed. Clearly, there is a gap between what’s happening in the lab and what’s happening in the doctor’s office. So in one sense, my question for Slamon was simple: How long do I have to stay disease-free – two years, five years, ten years? more? – until whatever I get can be taken care of?

Straightforward, independent, and celebrated for his accomplishments battling breast cancer, Slamon is particularly well equipped to offer this kind of perspective. For more than a decade, he bucked a cancer establishment focused on radiation and chemotherapy to pursue the targeted, gene-based research he passionately believed in.

The result was Herceptin, the first drug to come to the market targeting a specific genetic alteration that plays a role in causing tumors. In addition to saving lives, Herceptin established a new research paradigm and made Slamon one of the avatars of the new age of molecular biology. And even though he’s a leading member of the cancer-research establishment, he remains something of a maverick, unafraid to say what he thinks.

“It could mean the end of disease as we know it,” says Slamon. “That’s both exciting and scary.”

What I really wanted from Slamon was an expansion of an irresistible comment he made in casual conversation over veal and clams at Dominick’s on Arthur Avenue in the Bronx, several weeks earlier.

“Just as Einstein completely changed the way people look at the physical world, what’s happening right now is going to completely change the way people look at the biological world.”

There is a palpable sense in the scientific community that we are in the early stages of what will be an extraordinary age of discovery. “Everyone has talked about the last hundred years, with telecommunications and computers, as having been the information age,” says Dr. Lance Liotta, pathology chief at the National Cancer Institute. “But the next hundred years will be the age of biology. This is where the next information revolution will be.”

At Johns Hopkins, Dr. Bert Vogelstein, perhaps the country’s leading research specialist in colon cancer, is similarly buoyant. “When I was in medical school in the seventies, cancer was really a total black box, and we had no understanding of what caused it. That has completely changed. There’s been a revolution in understanding cancer at a basic molecular level. And the whole history of medical research is that once a disease is understood, it’s only a matter of time until that disease or its effects are ameliorated.”

And so, with the warmth of the L.A. sun on his face, Slamon is patiently laying out the newly developed battle plans in the war on cancer. The main target, he says, is the way the body’s cells talk to one another, how they communicate through a critical process called signal transduction. This process is to research scientists right now what the Internet is to investors; it’s the place where almost all the energy, money, and creative attention is going. Essentially, the goal is to disrupt or somehow alter the lines of communication when they’re being used by the disease.

When these lines of communication are working properly, they enable cells to perform their normal functions. When they break down, scientists now know, or when the “wrong” signals are sent, is when problems develop. Though the actual process is stunningly complex, the basic idea is relatively simple: Cells can send signals back and forth, using proteins as the messengers, based on information provided by the genes. (Manipulating this process is protein therapy; not to be confused with gene therapy, in which genes are introduced into the body. The 18-year-old who died in a clinical trial at the University of Pennsylvania was undergoing gene therapy.)

Everyone is taught in high-school biology that when you get a bug like the flu, the cells in the immune system recognize there’s a foreign object in your body, and they develop an offense, attacking the invader. But it’s understanding precisely how it all happens – what initiates the signal, where it comes from, what pathways are used, and which proteins and receptors are activated – that changes everything.

In the case of the flu, the body activates its defenses by producing proteins called cytokines or lymphokines. (It’s these proteins, by the way, that make you feel crummy and cause your fever.) The proteins deliver a message to the bone-marrow cells to proliferate; this in turn raises your white-blood-cell count, and the white blood cells then go attack the interloper and kill it.

When the infection is taken care of, the cytokines, the bone marrow, and the white blood cells all return to their normal levels. “The system’s got its own internal feedback, and it’s all beautifully orchestrated while you’re doing everything you normally do,” Slamon says.

But what really energizes him is the extraordinary implications. “The most profound orchestration, of course, is the way the entire genetic blueprint is laid out and followed from fertilization to delivery of an infant. Understanding how that happens is, literally, having the keys to life. And we’re there now. We’re breaking the entire code of the human genome so each gene will be identified and we’ll know what each one looks like. To use an analogy, you can’t read a book if you don’t first know the alphabet. Identifying the genes gives us an alphabet.”

The next challenge, in the language of Slamon’s analogy, is to use the alphabet to then read and understand the story. “If we know the genes and we understand their functions, we can then actually alter what happens in the body in profound ways,” Slamon says on the walk back across campus to his lab in UCLA’s Jonsson Cancer Center. “That’s both exciting and scary. If we put enough of this information together, it really could be the end of disease as we know it.”

Like most successful scientific innovators, Slamon is a zealot. He is convinced he can see things others can’t (or won’t); he has complete confidence in his vision; and, most important, he is a true believer in the power of science. And at least on part of this particular prophesy, he is not alone.

“We are going to see a global conquering of cancer in the next five to ten years,” says Dr. Carlos Cordon-Cardo, the director of molecular pathology at Memorial Sloan-Kettering.

The developments are “the equivalent of going from smoke signals to faxes and e-mails.”

The potent combination of knowledge (understanding which questions to ask) and technology (the means to actually get the answers) has begun to move science forward and make things happen at an unprecedented pace. When Slamon first began to look at genes involved in regulating cell growth back in the eighties, it was a cumbersome, exhausting process. He’d have to take a piece of tumor tissue that had been frozen in liquid nitrogen, grind it all up, liquefy it, extract the DNA, and examine one gene at a time for irregularities. This took days to accomplish, and in any event, there were only a handful of genes that had even been identified as being involved in growth.

Now not only are almost all of the body’s 70,000 to 100,000 genes identified – with hundreds so far believed to be involved in growth regulation – but a researcher can look at thousands of genes at one time thanks to something called micro-array technology. And the data can be analyzed relatively quickly on a desktop computer. It is only a matter of time before every doctor will have the equipment in his office to produce a genetic profile of each patient that could be used for prevention, diagnosis, and treatment.

“This really is a new era,” says Sloan-Kettering’s Cordon-Cardo. “This is the beginning of medicine that is much more scientific. It is going to change how we practice our specialities, how we diagnose, and how we orient our prognosis.”

Both Slamon and Cordon-Cardo say doctors will move away from hit-and-miss empiricism to tools that are much more precise. “Rather than simply looking at tissue and saying, ‘This is malignant, and I think it’s bad because the cells are not well differentiated and I’ve seen this many times before,’ we will have the technology to determine exactly what’s wrong,” says Cordon-Cardo.

“We will know why two people with what look like identical tumors under the microscope are responding so differently to treatment – why one is thriving and the other is dying. And we will be able to use this information to specifically tailor treatment for individual patients. I would say it is the equivalent of society going from smoke signals and banging on drums to faxing and e-mail. This is the kind of technological leap we’re looking at.”

Slamon says oncology has been at the forefront of the research because it’s such a profound disease process and the therapies currently used are so poor. “But this information we’re learning from the cancer battles will be really broad-based and far-ranging,” he says. “If we can control the genes, meaning that we can turn them on and off, think about the implications for virtually every disease, whether it’s diabetes, heart disease, or even aging.”

In the case of heart disease, people have heart attacks when blood flow to the heart is impeded and, as a result of this, part or all of the heart muscle dies. But, Slamon says, if scientists know which genes control tissue growth, they could theoretically engineer regeneration to replace the dead heart tissue. Similarly with diabetes, it would be possible to intercede to repair whatever’s wrong with the insulin receptors or in the signal-transduction pathways.

“The heart is an extremely complex organism that involves millions of cells connected in an intricate pattern that all have to contract together at the same time to push blood in the right direction,” says Dr. Andrew Marks, director of molecular cardiology at Columbia University. “So heart-tissue regeneration is, at best, a long way off.”

However, Marks points out that scientists do already understand some of the molecular mechanisms that control cell growth that results in blocked arteries. As a result, drugs to block these pathways have been developed and are already in clinical trials. In addition, markers are also being identified to help in both diagnosis and determining the course of a patient’s treatment. Studies have been published, for example, showing that people with an alteration of a receptor in the heart called beta-2 adrenergic suffer the most aggressive heart disease; so their treatment can be planned accordingly.

And then, there’s the aging process itself. “There’s an old saying in biology, which is ontogeny recapitulates phylogeny, which means the development of the individual recapitulates the development of the species. So at some point during your early gestation, you had a tail and webbed hands and webbed feet, because biology is built on itself. Through evolution, however, you don’t need the webbing anymore, so your genes take care of killing that growth. It’s called apoptosis, programmed cell death,” Slamon says while taking a tissue sample out of a large freezer, where it’s stored at 70 degrees below zero.

“Well, the same thing happens during aging. There’s programmed cell death. Cells are eventually lost, and when they aren’t replenished it results in organ failure. That’s what we call it. From nature’s point of view it’s probably an entirely appropriate function. You’re done, it’s time for you to go away and a new individual or group to come. Again, if we can interfere with or manipulate the signals, we can stop programmed cell death and stop the aging process. That’s the scariest part of the story, and I don’t want to be around to think about it.”

Surprisingly, the high-tech bet of the moment in research labs around the country is not directed at killing cancer cells, or even at trying to fix what’s broken in the cell that’s causing unregulated growth. While there are labs doing this kind of work, of course, the avenue of hot pursuit is an all-out effort to find an effective weapon to interfere with the signals involved in tumor growth. In order to flourish, tumors need nourishment; they need to be fed. This is accomplished by the formation of new blood vessels, a process called angiogenesis.

The idea is simple: Cut off a tumor’s food supply, and it can’t grow. Equally significant, and one of the key reasons angiogenesis is such an attractive target, is the hope that any successful treatment would be generic. All tumors, whether in the lung, breast, prostate, or colon, need nourishment. Scientists also believe angiogenesis may provide a big payoff as a point of attack because the cells involved in blood-vessel growth don’t mutate. Cancer cells, on the other hand, are quite volatile and do tend to mutate to form resistance to drugs, which is why strategies that specifically target tumor cells tend to fail.

The theory was first proposed by Dr. Judah Folkman of Children’s Hospital in Boston in the early seventies. However, back then, whatever the merits of the idea itself, the biology and the technology to take a serious shot at this strategy didn’t really exist.

But the precocious Folkman, who’s become almost a cult figure, thanks to a front-page New York Times piece about his work nearly two years ago, was denied a grant for his research by the National Institutes of Health even as recently as 1992. Today, however, there are nineteen separate clinical trials under way for anti-angiogenesis drugs, including Endostatin, one of the two that have come out of Folkman’s lab in conjunction with the company EntreMed (Folkman’s other drug is Angiostatin, not yet in trials).

When the Times piece by Gina Kolata was published, Folkman was still working only with mice. Nevertheless, DNA discoverer and Nobel winner James Watson, a towering figure in science, was quoted saying he believed Folkman would cure cancer in two years (that would be this May, although Watson claimed his comments were not accurately represented). Though Folkman’s work was no secret – and in fact, there were already anti-angiogenesis drugs that were farther along than his – the story caused a remarkable frenzy.

Folkman was overwhelmed by thousands of calls from seriously ill cancer sufferers pleading for help, and, of course, from the media. The episode is a stark illustration of the fine line researchers have to walk when they start making hopeful predictions about cancer treatments and potential cures. It’s also an indication of just how quickly things are moving: Less than two years ago, there was outrage at what was viewed as the excessive optimism of the Times piece.

Ironically, however, since Folkman is the recognized father of the field, researchers I spoke with do not believe his drugs are among the most promising. “Angiostatin and Endostatin are, in a way, a throwback to the old days,” says one scientist in the field. “By that I mean nobody, including Folkman, has any idea how they work. The mechanism of action is completely unknown.”

Using Folkman’s basic premise, however, there are a number of specifically targeted compounds in clinical trials now for which the expectations are much brighter. Biotech companies like Sugen and Genentech, just to name two, both have drugs in the later stages of patient testing.

While Sugen’s compound (SU5416) targets a receptor in the signal-transduction process, Genentech’s (anti-vascular endothelial growth factor, or anti- VEGF) is aimed, as you can tell from its name, at a growth factor. Again, going back to the basic biology of the cell and how one cell communicates with another, the effort here is to find a vulnerable point somewhere along the lines of communication and disrupt it.

As an adult, you don’t need to form new blood vessels, except perhaps in rare instances, such as to help heal a major wound. Nevertheless, cells have all the information required to carry out the process. And when there is a cancer, the renegade cells that are wildly reproducing set the cycle in motion. It’s known that certain conditions in the body can begin the signalling to start angiogenesis. A decrease in the flow of oxygen in a specific part of the body, for example, can cause the cells in that area to elicit VEGF.

This growth factor then instigates the production of endothelial cells, which actually begin to form the first part of the new blood vessel. As more and more of these cells are produced, they eventually coalesce into a tube. The building process is complex and requires at least three or four receptors working in concert to be successful.

“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.

Winning the Cancer War