Experts Find Role of Genes Crucial in Fighting Cancer : Medicine: Discoveries have propelled research into gene therapy, which has made its way into treatments.
When the “war on cancer” was declared by President Richard M. Nixon 20 years ago, researchers had a depressing mantra: “Cancer is not one disease, but 100.” No single cure for cancer will be found, they said. We will have to go through the long and agonizing process of finding a separate cure for each one.
But a series of startling and unexpected discoveries over the past half-decade have brought a marked change in that view. Molecular biologists have discovered two families of genes--one family that promotes growth of cancer cells and one that suppresses it--and, for the first time, researchers are beginning to understand the biology of how tumors grow from a single runaway cell into a life-threatening mass of tissue.
Although the geneticists already have discovered at least 60 genes that play roles in the transformation of healthy tissues into malignancies, it is becoming clear that only a handful of key genes, perhaps no more than five or six, play a role in the vast majority of cancers.
These and other discoveries have propelled cutting-edge research into gene therapy, some of which has already made its way into human treatment. Just as important, scientists are beginning to discern common patterns in the development of certain widespread cancers, such as colon, breast and lung--a finding that they hope could revolutionize the entire approach toward the dreaded disease. The crucial role played by these growth-suppressing and growth-promoting genes in the development of cancer and their uniqueness to the cancer process means that physicians have a potential new way to attack tumor cells without damaging healthy cells. Furthermore, a small number of therapies might have applications to a broad range of tumors, thereby limiting the number of new treatments that must be developed.
In addition, identifying these defective genes may provide a technique to diagnose the presence of tumors at a very early stage, when therapy is most effective.
Within the past year, oncologists have initiated at least four clinical trials of new therapies linked to the cancer genes, and the preliminary results appear promising. Researchers are also devising gene-based techniques to diagnose tumors, especially colon and breast cancers.
The notion that cancer has a genetic cause is not new. “The idea that mutations lie at the heart of cancer goes back close to 100 years,” said molecular biologist Bert Vogelstein of the Johns Hopkins University School of Medicine. “But only in the last decade has it been possible to get definitive supporting evidence for that idea.”
Detecting that evidence has been made possible by the development of the same genetic engineering techniques that, in recent years, have led to the discovery of defective genes for cystic fibrosis, muscular dystrophy and a variety of other inherited disorders.
“The cancer cell used to be a black box,” said oncologist Vincent T. DeVita Jr. of Memorial Sloan-Kettering Cancer Center in New York City. “But the lid of the black box has been opened and we can see the wheels turning inside.” He believes there is a good prospect of throwing some sand, and maybe even a monkey wrench, into those wheels to slow or halt them. But the wheels inside that box are not a smoothly operating mechanism like that of a fine pocket watch. Instead, scientists are now discovering that they bear more resemblance to a Rube Goldberg machine, haphazardly patched together from two different groups of genes that act at cross-purposes.
The first group, the tumor-promoting genes, or oncogenes, want to push and prod the cell toward runaway growth. These are genes that are normally activated during fetal growth and childhood to allow the body to grow larger, or during wound repair, and then shut down for the rest of the individual’s life.
At the same time, the second group, the tumor-suppressing genes or anti-oncogenes, are straining to hold back that growth and keep the cell in check. These genes are normally shut down during fetal growth and childhood, then activated later in life to maintain the status quo.
As long as the delicate balance between these two forces is maintained, cell growth is checked and the individual remains healthy. But this precarious tension between opposing forces in the cell is easily disrupted as the cells are buffeted by radiation, carcinogenic chemicals, viruses and bacteria. In such an event, growth of the cells spirals out of control, threatening the patient’s life by invading and disrupting healthy organs.
Perhaps an oncogene in a cell is activated by a flash of radiation from a medical X-ray. Or maybe an anti-oncogene is disabled by a benzene molecule from a back-yard barbecue. Either way, the cell is freed from its normal constraints and begins to proliferate.
“A damaged oncogene is like having the accelerator pedal (in a car) stuck to the floor,” said Vogelstein. “A damaged tumor-suppressor gene is like losing the brakes.”
But a car does not go plunging over a cliff the moment the accelerator sticks, and a cell does not become cancerous the instant a gene is mutated.
One mutation in an oncogene or anti-oncogene may start the cell on the road to cancer, but that mutation alone is not sufficient to get it all the way there. One of the principal lessons researchers have learned in recent years is that a cascade of genetic mutations must occur, most likely over a long period of time, before the cancer becomes life-threatening.
That is heartening news, said molecular biologist Curtis C. Harris of the National Cancer Institute, because “this gives us more opportunities to intervene” and block cancer development. “And if you can identify those early stages, you can intervene before the tumor becomes life-threatening.”
Perhaps the prototypical example of the cascade of mutations is found in colorectal cancer, which will strike 157,000 Americans this year and claim 60,500 lives, second only to lung cancer. In the last year, it has become the most thoroughly understood form of cancer, thanks largely to the work of Vogelstein. But researchers agree that similar processes occur in most other types of cancer and the lessons learned with colorectal cancer will have broad applicability.
Colon cancer is a valuable type to study because it takes many years to develop, allowing researchers to examine tumors in many separate stages. And the researchers have ready access to the tumors for the removal of biopsy specimens in which they can search for altered genes.
Moreover, at least 20% of all colorectal cancers can be traced to an inherited condition called familial adenomatous polyposis, giving scientists a window on the genetic processes involved in cancer. In August, teams headed by Vogelstein and geneticist Raymond L. White of the University of Utah reported that they had found the defective gene that causes the inherited disorder.
This gene, called APC, turns out to be a tumor-suppressor gene that is severely defective. Vogelstein and White believe it is inherited in a less damaged form in many other individuals, predisposing them to colon cancer even though they do not develop many growths, or polyps. In other cases, it may be damaged later in life by exposure to chemicals or radiation.
But cancer is a complex disease, and the discovery of a single gene is unlikely to translate into a cure. Vogelstein has shown that an oncogene called ras (because it was first found in rat sarcomas, a form of tumor) plays an important role in development of colorectal cancer, as do the loss of at least two other tumor-suppressing genes, one on chromosome 18 and another, especially important gene called p53, on chromosome 17.
While the precise sequence of these events can vary, their cumulative effect produces colon cancer. “The fact that it may take years for these changes to accumulate explains why colon cancer occurs mainly in people over 40 years of age,” Vogelstein said.
Their findings already are having implications for treatment. In examining tissues from tumors, Vogelstein and his colleagues have found that the number of defective genes they find is a good indicator of how patients will respond to therapy. In a study of 56 colon cancer patients, Vogelstein said, they found that “cancers that have acquired more changes have a higher proclivity to kill patients.”
Researchers are hopeful that this technique may be useful soon for detecting cancer in the early stages, when treatment is most successful. Vogelstein has found cells with a defective p53 gene in the urine of patients with bladder cancer. He and others are looking for similar defects in colon cells shed into feces, and the same process might prove useful in other cancers as well. These results suggest that tumors could be found before they are detectable by other means.
Such advances in understanding colon cancer are encouraging because a variety of evidence suggests that a similar cascade of genetic changes occurs in lung and breast cancer, both of which strike most commonly in middle age or later. In fact, that may be one of the key differences between such tumors and those of childhood and youth, including retinoblastoma, leukemias and lymphomas. Those apparently require fewer genetic mutations for full-fledged malignancy.
The case for breast cancer is particularly compelling. Last December, geneticist Mary-Claire King of UC Berkeley reported strong evidence for the presence of a breast cancer susceptibility gene analogous to APC. And in independent work, geneticist Mark Skolnick and his colleagues at the University of Utah reported that a benign condition known as proliferative breast disease--similar to the development of polyps in the colon--is a mark of increased risk of breast cancer.
These results suggest that it should be possible to identify women at unusually high risk of breast cancer, so that they can then be monitored more carefully for early detection of the disease.
Researchers have also identified at least two genes that play a significant role in metastasis of breast cancer. Last December, molecular biologist Pierre Chambon of the National Institute of Medical Research in Strasbourg, France, reported the discovery of an oncogene that is activated in the late stages of breast cancer. The gene is the blueprint for a protein that dissolves the tissue matrix that keeps the tumor confined.
This April, molecular biologists Lance A. Liotta and his colleagues at the National Cancer Institute reported the identification of a new tumor-suppressor gene associated with breast cancer. Healthy forms of the gene apparently prevent the metastasis of breast cancer cells. Its loss is correlated with poor survival and rapid death.
“Unfortunately, more than 60% of patients with newly diagnosed (breast) tumors have metastasis,” Liotta said. And in many cases this metastasis is undetectable by conventional means. A search of tumor cells for deletions of the new gene, he said, could identify those women who should be treated more aggressively to prevent relapse.
The discovery that cancer is so genetically complex is actually quite promising, said NCI’s Harris. “This gives us many more opportunities to intervene.”
One very promising way to intervene is through the tumor-suppressor genes. Last year, molecular biologist Wen-Hwa Lee and his colleagues at UC San Diego reported that the insertion of a tumor-suppressor gene called rb into human prostate tumor cells grown in dishes sharply reduced the ability of the cells to form tumors when injected into mice. The rb gene is one of the key genes in cancer, because defective rb genes have been linked to breast cancer, bone cancer and one form of lung cancer. Similarly, Vogelstein and his colleagues demonstrated that insertion of a healthy p53 gene, another of the half-dozen key genes, into cultured human colon cancer cells significantly reduced their proliferation.
Of course, modification of genes in human tumor cells is a goal that still lies far in the future, because of both the ethical constraints associated with genetic engineering in humans and the technical problems associated with the need to insert a healthy gene into every cell of a tumor.
But gene therapy may not be necessary. It may be possible, for example, to develop drugs that will mimic the activity of a tumor-suppressing gene such as p53. Alternatively, researchers may be able to stimulate tumor cells to produce additional quantities of tumor-suppressing proteins. And because p53 and some other tumor-suppressing genes play a role in many different types of cancer, a single drug could have broad utility.
A more immediate goal is to block the activity of oncogenes. Molecular biologist Dennis Slamon of UCLA has found an oncogene that plays a key role in the development of both breast and ovarian cancer. It produces a protein growth factor that binds to a specific site on the surface of tumor cells, called a receptor, thereby stimulating growth.
Slamon is treating women with advanced breast and ovarian cancer with monoclonal antibodies--special antibodies prepared from mouse tissues--that bind to the receptor for the oncogene, preventing the protein itself from binding and stimulating growth. Although the tests just started, preliminary results suggest that the monoclonal antibodies are slowing down tumor growth.
Similar therapies are being tested by oncologist John Mendelsohn and his colleagues at Memorial Sloan-Kettering Cancer Center in New York, who have developed an antibody that inhibits the action of an oncogene and tested it on 19 lung cancer patients. At Georgetown University in Washington, a group headed by Marc Lippman has begun clinical trials with 11 patients with breast and other types of cancers using pentosan polysulfate, a carbohydrate that halts the action of another oncogene known to stimulate tumor growth.
Finally, molecular biologist Thomas Waldmann of NCI is using monoclonal antibodies that target the receptor for a growth stimulating protein called interleukin-2. It has not yet been shown to be a classical oncogene, but it acts like one in a cancer called T-cell leukemia, which is normally lethal within 20 weeks. Waldmann has treated nine such patients with monoclonal antibodies so far and has found that eight underwent a partial or complete remission of the cancer--extremely encouraging results.
Although more work remains to be done, the future of therapy with oncogenes remains very promising, Harris said. “This society made an investment in the 1970s--the war on cancer,” he said. “At that time, a lot of scientists had a lot of questions about whether the money would be well spent. I don’t think that is a concern anymore.”
The Steps to Colon Cancer
The initiation of cancer is a complex process that involves the interaction of many genes. Some, tumor suppressor genes, normally serve to keep cell growth in check and must be either inherited in a defective form or inactivated by carcinogens in order for a tumor to be formed. Others have a normal function in the cell but promote the growth of tumors when they are mutated into oncogenes by a carcinogen. The example given is colon cancer, the second most common form of cancer, but a similar process occurs in other forms as well.
* Many people are born with a genetic defect in one of their tumor suppressor genes, leading to the formation of small polyps.
* When a mutation--caused by radiation or a chemical carcinogen--occurs in one of the polyp cells to form an oncogene, the polyps grow larger.
* A mutation inactivating a second tumor suppressor gene leads to formation of still larger polyps.
* A mutation in another tumor suppressor gene converts the polyp into a malignant tumor.
* A final mutation, perhaps one creating another oncogene, causes malignant cells to split off from the tumor and establish themselves elsewhere in the body.
