Molecular Advances Offer New Tools, New Hope For Cancer Studies

Sidebar: Cancer Resources The field of cancer research has been dramatically altered by advances in molecular biology. In some cases, investigators can tease out the precise molecular route by which cells turn cancerous and how those calls are affected by treatments. Researchers are working to understand the nuances of oncogenes, or cancer-causing genes. Others have located cancer susceptibility genes, providing hope for future screening methods and potential treatments. As scientists continue to search for better ways of detecting cancer, new disciplines are emerging. GROWING FIELD: Cancer genetics has "blossomed in the last few years," notes American Cancer Society’s Harmon Eyre. "The whole field of genetic understanding of cancer has blossomed in the last few years," says Harmon Eyre, executive vice president of research and cancer control at the American Cancer Society in Atlanta. "This includes the mapping of the human genome, and the isolation of the oncogenes and tumor suppressor genes." PREVENTIVE EMPHASIS: Columbia’s Frederica Perera says identifying causal factors is a key to effective intervention. One new field that has developed in recent years is molecular epidemiology. Taking advantage of scientists' ability to peer within DNA and cells, researchers such as Frederica Perera, a professor of environmental health sciences at Columbia School of Public Health, search for biological signposts of heightened cancer risk. "We need more emphasis on preventing cancer by identifying causal factors early on to be able to intervene effectively," she explains. "We focus on environmental factors, such as lifestyle factors like diet and smoking. We're concerned about workplace exposures, such as airborne carcinogens." Some cancers are influenced by genetic susceptibility, though by themselves, genetic factors cause only 5 percent to 10 percent of cancers. "Because of the tremendous advances in molecular genetics and biology, laboratories are yielding techniques to apply to blood and tissue samples in epidemiological studies, and getting answers to the risk of exposures to various contaminants," Perera states. In a 1992 study, she and colleagues monitored the occurrence of PAH-DNA (polycyclic aromatic hydrocarbons, which are byproducts of coal combustion and common in heavily industrialized areas) adducts in the bloodstreams of residents of Gliwice, Poland (F.P. Perera et al., Nature, 360:256-8). She found that the PAH-DNA adducts, in which PAH actually chemically bonds with DNA, are indexes of a population's exposure to PAHs. The PAH-DNA adducts rose and fell in conjunction with the city's seasonal change in hydrocarbon levels. In an unpublished study, she and her coworkers examined the effects of air pollution, measuring PAH-DNA adducts in mothers and newborns in a less polluted area of Poland. They saw molecular evidence that exposure to the PAHs adversely affected fetal growth and development. "The data we are coming up with from our studies, as well as from other groups, will be helpful in determining how much more sensitive children are to environmental exposure," she notes. "Data thus far indicates that the fetus in more sensitive to environmental damage than adults." She explains that PAH adducts are essentially DNA markers, or fingerprints, which can result in genetic mutations and cancer development. "We're looking for red flags-chemical signatures that may predict disease." American Association for Cancer Research Public Ledger Building, Suite 816 150 S. Independence Mall West Philadelphia, Pa. 19106-3483 (215) 440-9300, Fax: (215) 440-9913 E-mail: aacr@aacr.org World Wide Web: http://www.aacr.org 12,500 members President: Louise C. Strong Executive Director: Margaret Foti Journals: Cancer Research, Cell Growth & Differentiation, Cancer Epidemiology, Biomarkers & Prevention, and Clinical Cancer Research American Society of Clinical Oncology 225 Reinekers Lane Alexandria, Va. 22314 (703) 299-0150, Fax: (703) 299-1044 E-mail: asco@asco.org World Wide Web Site: http://www.asco.org 11,000 members Executive Vice President: John R. Durant President: James O. Armitage Executive Director: Robert E. Becker Journal: Journal of Clinical Oncology American Cancer Society 1599 Clifton Rd., N.E. Atlanta, Ga. 30329 (404) 320-3333/(800) ACS-2345, Fax: (404) 329-7530 E-mail: bjubb@cancer.org World Wide Web Site: http://www.cancer.org Executive Vice President: John R. Seffrin Journals: Cancer, Ca, and Cancer Practice In another recent study (D. Tang et al., Cancer Epidemiology, Biomarkers and Prevention, 4:341-6, 1995), she and coworkers showed that blood, lung, and breast tissue in smokers contained DNA fingerprints left by PAHs and other chemicals, suggesting that those with lung cancer have more molecular damage than normal individuals. She notes that in many cases, minority populations in inner cities are more frequently exposed to toxic environmental substances. At the same time, such individuals are more likely to be susceptible to disease owing to a variety of biological and environmental factors, including poor health care and nutrition. "One of our concerns is the risks to minorities and children, particularly to the developing infant and child. The developing fetus has less defense and capability to detoxify chemicals and repair DNA damage," she explains. "Molecular epidemiology has the potential to solve questions about environmental cancer causation because it can tell us about exposure at the individual level; it can tell not only what chemicals have gotten in [to a person's blood or tissues] but also what's been altered or damaged. "The field is still too young for us to say that we can test an individual and give him or her a precise measure of his or her risk," she says. "These measures are not validated yet; we need to know what these individual markers mean in terms of risk. We're collecting that information. Right now it can be useful in understanding risk in a population." Eventually, molecular epidemiologists may be able to establish a relationship between the quantity of adducts and other biomarkers in a person's blood or tissue and the likelihood of developing cancer, Perera predicts. Someone with an unhealthy level of biomarkers might decide to reduce his or her exposure, and even begin taking antioxidants-vitamins A, C, and E-that may inhibit adduct formation. Perera maintains that her biomarkers are mere fingerprints and not disease itself. Other researchers are hoping to find signs of genetic changes in DNA that prove a cancer is developing, spreading, or returning. FOUND LINK: Johns Hopkins’ David Sidransky’s team found evidence that genetic alterations may be associated with tumors. David Sidransky, an associate professor of otolaryngology/head and neck surgery and oncology at the Johns Hopkins Oncology Center, is searching for better ways to detect tumor cells. He's using molecular tests that detect cancer-causing mutations to improve the staging of tumors and the strategies of cancer surgery. Last year, he and his colleagues reported using a test to detect mutations in the tumor suppressor gene p53 in tissue surrounding tumors removed from head and neck cancer patients. Although pathology reports showed that the surrounding tissue had normal DNA and was cancer-free, p53 mutations-and cancer cells-were present in the surrounding tissue in 13 of 25 patients. More recently, he and his colleagues have been focusing on signs of genetic alterations in small pieces of repeated DNA markers called microsatellites (Notebook, The Scientist, Nov. 11, 1996, page 30). In some cancers, missing clusters of microsatellites indicate chromosomal deletions and genetic alterations, and perhaps cancer. The researchers used the test to find cancer in 19 of 20 symptomatic patients who later developed bladder cancer (L. Mao et al., Science, 271:659-62, 1996). And just last month, Sidransky's team reported finding genetic alterations linked to cancer in blood samples taken from patients with head and neck tumors. The early findings indicate that specific DNA alterations may be associated with large, advanced tumors that have spread. The genetic alterations found in the patients' blood were identical to the alterations from the tumor itself. This test, which works by identifying replication errors such as chromosomal deletion in the DNA of cancer cells, might help identify patients with poor prognoses who may benefit from aggressive therapy. He contends that the "leap of knowledge in understanding tumor genetics is a revolution of sorts," pointing to the ability to use these genetic changes to develop tests and make early diagnoses and assessments of tumor burden. He boldly predicts that "we're reaching the scenario in which instead of being a fatal disease, it [cancer] will become a chronic, treatable disease, comparable to having a heart attack or stroke. We will remove the tumor before it becomes large enough to become life-threatening." Recent announcements of the location of a prostate cancer gene (J.R. Smith et al., Science, 274:1371-74, 1996) and the successful use of gene therapy in ovarian cancer, albeit in an animal model (K. Behbakht et al., American Journal of Obstetrics and Gynecology, 175:1260-5, 1996) underscore the rapid pace by which molecular genetics has begun to change the field of cancer research. The war on cancer took major leaps in the last few years with the seemingly weekly discovery of new disease susceptibility genes, many of which play roles in cancer development (see story on page 1). While efforts continue through the National Institutes of Health's National Center for Human Genome Research (NCHGR) and the Human Genome Project-the government's $3 billion, 15-year attempt to map the entire complement of human genes-the discoveries in the last few years of hereditary colon, breast, and ovarian cancer susceptibility genes stand out as major accomplishments. "Now we have the molecular tools to dissect the cancer cell and identify the abnormalities and categorize them," says the American Cancer Society's Eyre. "This has given us the ability to look at and understand the gene abnormalities that give rise to disease." These discoveries were necessary before scientists could begin to synthesize drugs, replace the products of defective genes, or even replace genes with gene therapy. "Such therapy will be big time in the future," he predicts. Johns Hopkins' Sidransky contends that within the last decade, scientists have sped up the pace of identifying cancer genes, "which is already having effects in the clinic, allowing patients with inherited predispositions to get tested for colon cancer and hereditary breast cancer. This tremendous advance in studying the genome is beginning to have impact in the clinic. These genetic changes are beginning to be used as diagnostic markers. We hope ultimately that by understanding these genetic changes, we will begin having better treatments." NCI's close collaboration with NCHGR and its key role in the Human Genome Project demonstrate that the institute is betting on genetic medicine to lead the cancer fight into the next century. NCI is launching two specific projects in this area: the Cancer Genetics Network (S. Benowitz, The Scientist, July 22, 1996, page 1; Notebook, The Scientist, June 10, 1996, page 30) and the Genome Anatomy Project. The network will be a cooperative effort between NCI and scientists across the nation to offer genetic testing for cancer susceptibility in a research setting. The anatomy project is a new initiative to develop technologies for characterizing the genetic fingerprints of cells and assessing their tumorigenic potential. Others hope to use the body's immune system to fight cancer. Along with this method, some scientists are looking to gene therapy -- actually replacing aberrant or missing genes -- to stem cancer. NEW VACCINES: NCI's Steven Rosenberg is conducting clincal trials of an immunization against melanomas. NCI surgery branch chief Steven Rosenberg contends that the "whole field of immunotherapy -- harnessing the body's immune system to fight disease -- has been turned around in the last several years." For the first time, he says, "we know the exact molecular identity of the genes that code for cancer antigens-proteins that are recognized by the immune system, and potential targets of cancer vaccines." Last month, Rosenberg published his strategy for immunotherapy using these new gene products (S.A. Rosenberg, Journal of the National Cancer Institute, 88:1632-44, 1996). "We've taken that gene and engineered vaccinia and adenoviruses to immunize patients against the very genes that represent tumor antigens. It's put the issue of cancer vaccines and active immunization on firm footing," he comments. His Phase I cancer vaccine trials involve some 140 patients in studying the safety and efficacy of melanoma vaccines, to determine which viral delivery mechanism is most effective. He's also using interleukin 2, a natural substance that may enhance the tumor fighting abilities of the vaccine, in trials. Some scientists are exploring the use of gene therapy against cancer. Though "gene therapy for human cancer has accomplished little to date, it may be the only promising approach to deal with human solid tumors," notes Jeff Boyd, an associate professor of obstetrics and gynecology at the University of Pennsylvania. He recently reported successfully using gene therapy to treat mice with ovarian tumors. Rather than replace a malfunctioning or missing gene, cancer gene therapy aims to deliver cancer-killing agents in combination with other products directly to the tumor. Boyd asserts that the development of dramatically new and improved chemotherapy drugs for solid tumors isn't likely, and he expects gene therapy to take on a greater role in cancer treatments in the future. For now, however, the field remains in its infancy. Some scientists believe that a key to learning how to combat the cancer cell lies in understanding how cells die. Samuel Hellman, A.N. Pritzker Distinguished Service Professor at the University of Chicago and coauthor, along with Rosenberg and Yale Cancer Center director Vincent T. DeVita, Jr., of one of the classic cancer textbooks in the field (Cancer: Principles and Practice of Oncology, Philadelphia, J.B.Lippincott, 1982) urges scientists to "take advantage of things that affect tumor growth, such as cytokines, interleukins, and tumor necrosis factor." He believes that research to understand apoptosis-programmed cell death-will yield insights to better ways to kill cancer cells. "Up until 20 years ago, we didn't recognize apoptosis-now we know it's a fundamental cell process, an active process of programmed cell death. We know that tumor cells frequently lose this process," especially when the tumor suppressor gene p53 is mutated or missing, Hellman says. Normally, p53 acts to sense genetic damage and then lead a cell to its own death, a cascade of chemical events necessary to kill the cell. "But it can be manipulated-there are biologic pathways that will enhance it, and those that will prevent it. It's a new area which has been barely touched but which I think will be fruitful." Chemotherapy drugs frequently work by damaging DNA, triggering p53 to initiate apoptosis. Hellman contends that such research will allow scientists to "better predict what tumors are doing or have done. We'll be able to get a molecular profile of tumors which will tell us which tumors will spread, which have already, and which won't. We'll be able to tailor treatments to individual tumors." Yet, as is true of all experimental therapies, only time and effort will tell if they are successful. In the meantime, as scientists continue to unlock the secrets of the cancer cell and solve the molecular mysteries behind the genetic changes leading to cancer, researchers will begin to understand how to use such knowledge to take the next step: devise better therapeutics and improve patients' lives.

Molecular Advances Offer New Tools, New Hope For Cancer Studies

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