WASHINGTON—Oncology is in transition from its traditional methods of diagnosing and treating cancer to a reliance on molecular changes within cells—and the science behind this paradigm shift will lead to new drugs to attack precancerous conditions as well, several cancer researchers said at a congressional briefing.
Carcinogenesis occurs over many years, said Andrew J. Dannenberg, MD, director of cancer prevention, New York Presbyterian Hospital-Cornell, and professor of medicine, Weill Medical College of Cornell University. Advances in genetics, biochemistry, and cellular biology have begun to identify cellular changes and molecules that can be used to diagnose, classify, and treat cancers, Dr. Dannenberg said.
A key finding for the future is that "in virtually any tissue one can think of, there are molecular changes that occur in association with precancer," he said.
"We tend to talk about anatomic diagnosis—about cancer of the breast, cancer of the lung, cancer of the colon," said Larry Norton, MD, head of the Solid Tumor Division, Memorial Sloan-Kettering Cancer Center, and president of the American Society of Clinical Oncology.
This sounds reasonable, he noted "until you start talking about infections. We never say any more, as doctors, that someone has an infection of the lung; we say they have a streptococcal infection of the lung. We talk about causative organisms because that organism—whether it is involved in the lung, liver, skin, or any other part of the body—will be treated with the same antibiotic. Classifying things by their cause is a much more useful way of classifying a disease." Both cancer researchers spoke during a Capitol Hill briefing to House and Senate staff members working on health issues. The meeting was organized by the National Coalition for Cancer Research (NCCR) as one of its regular educational efforts known as "Cancer 101."
Current cancer therapies are complicated, often toxic, require specialists to administer them in specialized settings, and need supportive care, Dr. Norton said. "We can’t tell in an individual case if someone is going to get better or not, or whether the cancer is going to recur. And we can only tell if we’ve been successful by looking to see if the lumps are coming back," he said. "This is currently where we are, and we shouldn’t be too excited about it. Fortunately, we are in the process of changing that."
Researchers and drug developers are searching out genetic and molecular changes that can be used for more specific cancer diagnosis, classification, and treatment, Dr. Norton said. Each cell type has a specific pattern of gene expression in its normal form and different patterns in cancer. It is by identifying and understanding specific variations that researchers expect to change how oncology deals with the disease.
"You can see this is an entirely different way of looking at the cells. It is not just saying this cell is growing faster than that cell, but actually saying what is making it grow faster," Dr. Norton said.
He cited imatinib(Drug information on imatinib) mesylate, also known as STI-571 (Gleevec), an oral agent recently approved for the treatment of chronic myelogenous leukemia, as an example of the targeted, nontoxic cancer therapies that will make their way into clinical practice based on rational drug design.
Imatinib targets and blocks the functioning of an abnormal protein, Bcr-Abl. The protein is created as the result of a reciprocal translocation between chromosome 9 and 12 (the Philadelphia chromosome), and it leads to an uncontrolled proliferation of white blood cells.
Cancer Prevention
"Where we are going is to make molecular diagnoses, to classify cancers by the molecules that are driving them," Dr. Norton said. "As we know more about how cancers work, therapy and prevention become the same topic. The same interventions that can work for therapy can work for prevention."
Indeed, Dr. Dannenberg said, the current focus on drug development is limited to existing cancers. "In my opinion, that needs to shift in emphasis, not just to target the person who has cancer, but to develop more effective therapies for the individual who has precancer," he commented.
Dr. Dannenberg cited celecoxib(Drug information on celecoxib) (Celebrex)—approved for the reduction of adenomatous colorectal polyps in patients with familial adenomatous polyposis (FAP)—as an example of how precancerous cells might be treated early in carcinogenesis to prevent them from becoming cancerous.
Celecoxib inhibits cyclooxygenase-2 (COX2), an enzyme whose overexpression is linked to FAP and the development of colon and rectal tumors, he said. The preventive powers of COX2 inhibitors are currently being tested in several other precancerous conditions, including leukoplakia.
"Importantly, numerous other agents are being evaluated as treatments for precancer," Dr. Dannenberg said. "And ultimately, it seems likely that combinations of agent that target different molecules that are aberrant during carcinogenesis are likely to be more effective than any single agent."
However, he added, the Food and Drug Administration needs to offer more encouragement to industry to develop drugs to halt carcinogenesis in the precancerous stage.
"For the pharmaceutical industry to invest, it needs to understand how success can be achieved," Dr. Dannenberg said. "It is well understood from the standpoint of treating cancer, but more needs to be done to develop guidelines that will facilitate the development of drugs to treat precancer."
20 Years of Research Bear Fruit
It remained for Lynn Mara Schuchter, MD, to point out to the Congressional staffers the importance of federal research funds to the successes so far and the future potential for targeted drugs to treat and prevent cancer. She cited the years of fundamental research that led to the development of trastuzumab(Drug information on trastuzumab) (Herceptin), now approved for treating HER2-positive breast cancer.
"Years and years of basic science went into studying a growth factor [HER2] that turned out to be very relevant to breast cancer; then, very specific therapies were developed to target this growth factor," said Dr. Schuchter, associate professor of medicine, University of Pennsylvania Cancer Center. "Funding in the basic sciences over the last 20 years is what has truly revolutionized cancer now in terms of diagnostics and treatment. We are really seeing the fruition of that funding."
