U.S. Army Medical Research and Materiel Command

September 28, 2002

MOLECULAR TARGETS: BREAKING THE CHAIN OF CANCER CAUSATION

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Jennifer Goldberg phone 212/886-2200, email jgoldberg@cwg.com;
Gail Whitehead, Public Affairs Coordinator, phone (301) 619-7783, email gail.whitehead@amedd.army.mil;

Research Results from the "Era of Hope "Department of Defense Breast Cancer Research Program Meeting

ORLANDO, September 26, 2002 - Increasingly, anticancer treatments target specific genes, the proteins they express, and the molecular pathways they influence in an attempt to interrupt the complex cascade of events required for malignancies to take hold and flourish. Research described at the "Era of Hope" Department of Defense Breast Cancer Research Program meeting focuses on several such targets. In one particular study, researchers have produced a compound that interferes with a mutant protein, which is often detected in aggressive tumors.

Novel Gene Splicer Targets Mutant Protein Implicated in Aggressive Breast Cancer

Scientists have engineered an agent called a ribozyme that reduces the growth of human breast cancer in mice by decreasing the expression of the protein EGFRvIII - a mutant variant of epidermal growth factor receptor (EGFR) - that is found in 60% of invasive breast cancers but not in normal breast cells.

"The ribozyme we developed targets the middle step in the process that leads to expression of a tumor-associated protein like EGFRvIII - which is when RNA manufactures the protein," said Careen K. Tang, Ph.D., an associate professor at Georgetown University Medical Center in Washington, D.C., and a principal investigator of the study. There are two other stages at which treatment can interrupt the expression process - when a gene makes RNA, and when expression of the protein manufactured by the RNA is involved in a chain of events that promote cancer, explained Dr. Tang.The ribozyme synthesized by the Georgetown team homes in on the mutation in EGFRvIII: a deletion in the middle that shortens it by 801 base pairs. Where these base pairs are missing, the truncated gene is united by a genetic code that's not repeated in the normal receptor. The ribozyme seeks out this unique fusion junction, where it acts as a kind of molecular scissors, cleaving to the RNA and thus blocking expression of the undesirable protein.

In earlier research, Dr. Tang and her colleagues confirmed the tumor-stoking activity of EGFRvIII by injecting mice with MCF-7 human breast cancer cells containing the mutant protein. Tumors in those mice grew faster and larger than tumors in mice injected with MCF-7 alone. The researchers recently demonstrated that their ribozyme also reduces EGFRvIII expression in tumors grown from another human breast cancer cell line in mice. EGFRvIII is particularly potent because it is "on" all the time, Dr. Tang noted. Unlike most proteins, it doesn't have to bind to another molecule to become active.

"EGFRvIII is a good therapeutic target because it interferes with tumor cells but not with normal EGFR. The real challenge will be delivering the ribozyme to specific tumor sites," Dr. Tang commented.

Until that delivery problem is solved, Dr. Tang's group will continue to study EGFRvIII and explore different strategies to suppress it, such as use of small molecules like tyrosine kinase inhibitors, which target the activity triggered by EGFRvIll expression rather than the protein itself.

"Era of Hope" is a forum for the presentation of research supported by the US. Department of Defense's Breast Cancer Research Program (BCRP), an unprecedented partnership between the military, scientists, clinicians, and breast cancer survivors. Since 1992, the BCRP has been working to prevent and cure breast cancer by fostering new directions in research, addressing underserved populations and issues, encouraging the work of new and young scientists and inviting the voice of breast cancer survivors to be heard in all aspects of the program. One of many congressional research programs managed by the US. Army Medical Research and Materiel Command, the BCRP has received more than $1.3 billion to date from Congress for innovative breast cancer research.