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OCTOBER 21, 2005
  Penn Researchers Lay Foundation for Herceptin’s Most-Recent Promise
   

(Philadelphia, PA) - Yesterday three new studies were released describing the benefits of Herceptin, already used to treat advanced cancer, in fighting an aggressive form of early breast cancer. The results of these trials were so promising that the National Cancer Institute stopped the research ahead of schedule earlier this spring to make the findings public. Pioneering research conducted at the University of Pennsylvania School of Medicine over the last two decades has laid the foundation for these most-recent announcements.

The emerging story of new classes of “targeted” drugs like Herceptin-able both to treat advanced cancer and prevent cancer development and reoccurrence-illustrates that progress in science is rarely a “eureka” moment of singular discovery. The reality is much more complex. In this case, progress is cumulative. It is the product of more than 20 years of extensive research and contributions from multiple teams of researchers building on the initial work of Mark Greene, MD, PhD, the John Eckman Professor of Pathology and Laboratory Medicine at Penn, and his former student at Harvard University and now colleague, Jeffrey Drebin, MD, PhD, Chief of the Division of Gastrointestinal Surgery, also at Penn.

Cancer treatment is in a new era. Conventional chemotherapy targets the DNA of dividing cells, which increases the risk of harm to non-cancerous tissue. Mutations leading to drug resistance are also a consequence. The newer outlook is called targeted therapy and is aimed not at the DNA but at proteins made by genes, specifically receptor molecules found on the surface of tumor cells.

Some targeted therapies rely on monoclonal antibodies, proteins produced in the laboratory that bind only to the cancer cells in a patient, seeking them out and destroying them, without harming normal cells. Herceptin, which is effective in 20 to 30 percent of breast cancers, is a monoclonal antibody. It targets a specific protein found on the surface of breast cancer cells called HER-2/neu, by working only against breast cancers that have too much of this protein.

The road to Herceptin’s success goes back to early work of Greene and Drebin in 1984. In that year, in collaboration with a group at MIT headed by Robert Weinberg, they demonstrated how HER-2/neu caused cells to become cancerous. Working with mice, Greene and Drebin showed that an anti-HER-2/neu monoclonal antibody could be a therapeutic weapon against cancer. In 1985, Greene and Drebin found that mouse monoclonal antibodies caused malignant neu cells to transform back into essentially normal cells by disabling the protein that actually caused the malignancy. These efforts represent the initial observation for targeted therapy’s promise. Moreover, the antibodies worked without additional chemotherapy and had no harmful effects on normal cells. Initially Greene and Drebin worked on animal cancers but showed this was relevant to human disease as well since other researchers found that some of these antibodies were able to bind to human tumor cells, thus setting the stage for possible application against cancer in humans.

Soon after, in 1987, two groups, one from UCLA and another from the Netherlands, published an important observation that some human breast tumors contained increased HER-2/neu. This discovery and the pioneering work of Greene and Drebin paved the way for several laboratories to begin development of monoclonal antibodies for human HER-2/neu. Herceptin is one such antibody.

In 1986 through 1990 Greene and Drebin went a step further and showed that using two antibodies, one that bound one site of the neu protein and another antibody that bound to different surfaces together had an even better result than simply using one antibody. Ten years later, in 1998, they were awarded a patent for this “two antibody” approach. Currently, clinical trials for this synergistic line of attack are underway and may represent even more effective cancer-fighting success.

Greene also found that neu would often associate with another protein called EGFR to create very aggressive tumors. His group showed that this new transforming complex built of neu and EGFR could also be disabled. When his group treated tumors caused by this complex with antibodies for HER-2/neu and another for EGFR, they could dramatically inhibit tumor growth. Antibodies for EGFR therapy have also reached the market as a consequence of similar work done by John Mendelson and colleagues then at the University of California at San Diego.

In 1995, Makoto Katsumata, PhD, and colleagues in Greene’s group, showed that they could prevent tumor emergence in a genetically engineered animal model they had developed in which breast cancers develop in female mice in a similar manner to human cancers. Administering antibodies to the mice prior to the development of cancer effectively prevented the tumors from even arising in a significant proportion of treated animals. These studies indicated that targeted therapy could also be used in individuals who had a tumor removed and would prevent emergence of tumors that had spread at the time of surgery or before.

“We’re proud to have played a role in helping to bring real promise to the lives of women who have breast cancer now and those who be diagnosed in the future,” says Greene. “This long process shows that persistence, open sharing of information, and cooperation are the roles of academics. The targeted therapy of proteins that cause malignant cell behavior is simply the first step, we must now turn our attention to eradicating the more advanced cancers altogether. ” Drebin adds, “Medicine is essentially about teamwork. Dedicated people working together can and do make real differences in the lives of other human beings.”

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