Targets for Therapy
Michael Press painstakingly explores the link between genes and breast cancer.
by Eva Emerson
Basic biological research plants theoretical seeds. Fostering these seeds to fruition-research that can be applied to patient care-takes focus, time and more than a bit of perseverance.
USC/Norris pathologist
and cancer researcher Michael Press, M.D., Ph.D., knows about
perseverance. Over the years, his careful studies of cancer-causing
genes have helped transform a basic finding in rats into an important
new tool for doctors and breast cancer patients. The work has
also provided a target for innovative therapies against the most
advanced breast cancers.
In 1981, laboratory biologists identified a gene, called "neu," in a rat tumor. When mutated, the gene worked like a switch, turning normal cells into cancerous ones. Four years later, scientists found a similar human gene, which they called Her-2/neu.
Since then, evidence has mounted that the Her-2/neu gene may be altered in 25 percent or more of breast cancer tumors. What's more, Press has shown that patients with the altered form of the gene tend to have the most aggressive disease. In other work, Press has revealed the importance of Her-2/neu as a marker of tumor aggressiveness in cancers of the ovary, endometrium and salivary glands.
"Her-2/neu is an example of an oncogene or cancer gene," explains Press. "Cancer genes accelerate the growth of malignant cells."
Like many oncogenes, the normal version of the Her-2/neu gene is harmless and plays a key role in early development and cell growth. But Press has found that many tumors contain too many copies of the Her-2/neu gene, which may also carry genetic changes that cause the gene to be turned on all of the time. Combined with other potent alterations in a cell's genes, this leads to the uncontrolled growth of cancer.
Currently, most women are not tested to see whether their breast cancer involves Her-2/neu or not, something that Press predicts will change in light of the latest research. The more scientists learn about Her-2/neu, the more critical it will be to know the status of Her-2/neu-particularly when considering which treatment to use on a patient.
Working with former USC scientist Franco Muggia, M.D., now at New York University, Press found that women with breast tumors containing Her-2/neu alterations are more likely to respond positively to the anti-cancer drug Taxol.
Press and Christy Russell, M.D., assistant professor of oncology, plan to follow up on this result with a clinical trial. In the upcoming study, half of the breast cancer patients will be treated according to the results of what Press calls "the molecular diagnosis"-whether they carry the Her-2/neu marker. The other half will be treated according to standard clinical practice.
"When you say 'breast cancer' you're not talking about a single disease," says Press. "There are a variety of types of breast tumors that you can discern by looking at tissue samples. It turns out, you can further divide these into tumors that carry certain genetic changes."
A challenge will be making sure that clinical laboratories provide quality testing for the new tumor marker. In a study, Press has shown that commercial labs use tests for the molecular change that vary widely in sensitivity, and thus reliability. Experience, such as that found at a research setting like USC/Norris, is key to providing reliable testing, he says.
With his brother Oliver Press, an oncologist at the University of Washington in Seattle, M.D./Ph.D. student Jinha Park, Anna Wu, a collaborator from City of Hope Medical Center, and others, Press has recently devoted more energy to developing novel biotherapies that target Her-2/neu. He plans to use a strategy similar to that used with the drug Herceptin, the first therapy ever designed to take advantage of genetic inconsistencies between cancer and normal cells-the very flaws that allow tumors to develop.
Using that strategy as his guide, budding physician-scientist Park has developed a number of antibodies that bind to Her-2/neu receptors on breast cancer cells. The team plans to engineer the antibodies to pack a tumor-killing punch of toxins or radiation. Since the antibodies are expected to attack only tumor cells, the team expects fewer side effects than with current therapies.
Press cautions they are at an early stage with the new therapy-still in the midst of test-tube experiments. But, as he well knows, focus, time and perseverance help laboratory wonders evolve into patient care breakthroughs.