September 10, 1999

Researcher probest breast cancer drug’s basic mechanisms

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Dr. Carlos Arteaga

Researcher probest breast cancer drug's basic mechanisms

A Vanderbilt-Ingram Cancer Center physician-scientist is one of four researchers in the world awarded peer-reviewed grants from the maker of Herceptin to learn more about the basic mechanisms of action of the monoclonal antibody, which made headlines when approved as a breast cancer therapy last year.

The two-year, $250,000 grant from Genentech Inc. will fund a study of the biochemical and molecular mechanisms of action of Herceptin on human tumor cells in the laboratory of Dr. Carlos L. Arteaga, Ingram Professor of Cancer Research and leader of the Cancer Center's Breast Cancer Program.

"Genentech established this competitive funding exercise because the company believes that understanding how Herceptin works is crucial to understanding how to use the drug, for how long to use it and in which patients," Arteaga said.

Other institutions awarded grants from Genentech to fund additional basic research into Herceptin are the University of California-Los Angeles School of Medicine; the Weizmann Institute in Rehovot, Israel; and Memorial Sloan-Kettering Cancer Center.

Herceptin is a monoclonal antibody that targets a specific protein, the HER2/neu (erbB-2) receptor, which resides on the tumor cell surface. This protein is a key player in the message chain that triggers the unchecked cell division that characterizes cancer. In 20-25 percent of breast cancers, a genetic abnormality results in excess amounts of HER2/neu receptor, which provides a proliferation or survival advantage to those tumors.

Encouraging results from Phase III studies — conducted at several centers including the VICC — were announced in early 1998 and led to U.S. Food and Drug Administration approval of the drug late last year for treatment of women with metastatic breast cancer that overexpresses the HER2/neu protein.

The news is exciting because the segment of breast cancers in which HER2 is overexpressed tend to be particularly aggressive and because Herceptin is the first of a new class of drugs specifically targeting cancer cells to become available.

However, much is still unknown about the precise ways in which Herceptin works to block HER2's signals from reaching the nucleus and promoting tumor cell viability.

"The effects of the antibody are probably multi-factorial," Arteaga said. "Some of those factors may be related to Herceptin's effects on the cell cycle and may be studied in cell culture studies. Others may depend on host responses and be more obvious in animal models or multi-cellular experimental systems. Our lab will be focused initially on the cell-autonomous effects, both in vitro and in vivo."

Herceptin is currently FDA-approved for use as a first-line therapy in combination with the chemotherapy agent paclitaxel, and as a single agent for use in second- and third-line therapy (treatment in women whose cancer has recurred after initial therapy or has not responded to it).

"As a single agent, Herceptin works in less than 20 percent of patients with HER2 overexpression," Arteaga said. "Additional basic research is needed to help understand the mechanisms of resistance to Herceptin, which might be bypassed with additional biological agents used in combination with the antibody."

Meanwhile, clinical studies are ongoing to test the effectiveness of Herceptin in combination with other chemotherapy agents, and the National Cancer Institute plans to expand Herceptin clinical research to include other types of tumors also associated with elevated HER2 levels.

Among these studies, the Vanderbilt-Ingram Cancer Center is a participant in a multi-center trial examining Herceptin in combination with the chemotherapy drug docetaxel as first- or second-line therapy for metastatic, HER2-overexpressing breast cancer. In addition, the VICC is piloting a trial of a novel combination of Herceptin with the anti-estrogen drug tamoxifen, with the goal of bypassing resistance to anti-estrogens that is associated with HER2/neu overexpression in some breast tumors.

For more information about cancer clinical trials, contact the Vanderbilt-Ingram Cancer Center's Information Program at 1-800-811-8480 or the National Cancer Institute's Information Service at 1-800-4-CANCER.