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.
NEW YORKA 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.
In vitro studies showed that 17-AAG stopped cell growth but did not result in much apoptosis. When paclitaxel was added to the cell cultures, however, apoptosis was greatly enhanced.
In a series of experiments with genetically engineered murine models of breast cancer, Dr. Rosen found that 17-AAG was able to destroy HER-2 and AKT in the animals’ tumors at nontoxic doses. When given in combination with paclitaxel, he reported, cells were profoundly sensitized to the taxanes, and there was a significant increase in survival.
"The real key to using this in humans is that we can give this combination in mice without untoward toxicity, in fact, without any adverse toxicity," Dr. Rosen said.
An additional potential advantage of 17-AAG/paclitaxel, he noted, is that the combination should work in tumors where the PTEN gene has been deleted, since AKT is a direct target as well as being affected by proteins higher in the cell pathway.