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Antibiotic Inhibits Key Protein in Two Cancer Cell Pathways

Antibiotic Inhibits Key Protein in Two Cancer Cell Pathways

NEW YORK—A drug that targets a protein important to two cancer cell
pathways will be tested in combination with paclitaxel (Taxol) in phase II
clinical trials slated to begin soon at Memorial Sloan-Kettering Cancer Center
and the Mayo Clinic, Neal Rosen, MD, PhD, said at a "Meet the
Experts" media briefing sponsored by the American Society of Clinical
Oncology.

The ansamycin antibiotic to be tested, 17-AAG (17-allylaminogeldanamycin),
inhibits the AKT protein. This protein triggers both cell growth deregulation
and apoptosis desensitization, said Dr. Rosen, head of research in molecular
oncogenesis, Sloan-Kettering Institute, and professor of cell biology and
medicine, Weill Medical College-Cornell University, New York.

A serine kinase, AKT is a signaling protein that is downstream on the cell
pathway from HER-2, EGF, and other growth factor receptors. "We know that
activating AKT deregulates growth," Dr. Rosen said. "But at the same
time, by other mechanisms, activating AKT shuts off apoptosis. It desensitizes
the cell to cell death. This is very bad, since it activates two switches for
cancer development."

Loss of PTEN

PTEN, a gene that downregulates AKT activity, is missing or deactivated in
many cancers, including gliobastoma and prostate and uterine cancers, Dr. Rosen
said. Activation of the EGF receptor in glioblastoma together with the loss of
the PTEN gene, he said, "results in a profound activation of AKT, which
may be in part responsible for why this tumor is so refractory to chemotherapy
and radiation therapy."

A number of pharmaceutical companies are interested in developing drugs that
will turn off the AKT enzyme directly, Dr. Rosen said. The agent he and his
colleagues are investigating (17-AAG) is a natural product derived from a
bacterium that binds with the heat shock protein HSP90. This protein is
required to fold some proteins into the correct conformation to become active.

Analysis of the HSP90 protein by Dr. Rosen’s group revealed that it has a
pocket that appears to be essential to the folding process. "But if this
pocket is occupied by this drug, the folding doesn’t take place," he
observed. "Instead, the proteins that require this for folding get
destroyed." Among the proteins destroyed in this way are HER-2, EGF
receptor, and AKT, he said.

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