Dr. Carlos L. Arteaga, Ingram Professor of Cancer Research.
VICC group finds marker for cancer drug action
A group of Vanderbilt-Ingram Cancer Center scientists has identified a potential marker for activity of Herceptin and other drugs designed to block HER2/neu pathway. This signaling pathway is overexpressed in about a quarter of human breast cancers.
Writing in the journal Nature Medicine, the investigators describe their work showing that the Akt kinase, a major mediator of HER2/neu activity, contributes to tumor cell proliferation by keeping the cell cycle inhibitor p27 out of the tumor cell nucleus.
Conversely, inactivation of the HER2/neu and/or Akt redirects p27 to the nucleus, the investigators report.
“Therefore, this information could generate possible markers of anti-tumor drug action that should allow us to better select and follow patients undergoing treatment with rational molecular therapies against HER2/neu or Akt,” said Dr. Carlos L. Arteaga, Ingram Professor of Cancer Research.
The work, supported by the National Cancer Institute, the Vanderbilt-Ingram Cancer Center and Genentech, appeared on the Nature Medicine Web site in September and in print in the October 2002 issue.
Since the report’s appearance online, Arteaga has received numerous e-mails from investigators across the country interested in using antibodies against phosphorylated p27 as a marker of drug action in clinical trials with anti-signaling drugs.
HER2/neu is a member of the EGF receptor family, which is involved in tumor cell proliferation and survival and has become the target of several novel anti-cancer drugs.
Signals from outside the cell activate HER2/neu which, in turn, activates the Akt kinase. Akt attaches a phosphate to a threonine residue in p27. This change induced by Akt prevents p27 from entering the nucleus, where it normally inhibits tumor cell progression in the cell cycle. If the antibody Herceptin or other inhibitor inactivates HER2/neu, p27 enters the nucleus and stops tumor cell growth. Therefore, as a result of HER2 and Akt activation, p27 is retained in the cytoplasm of the cell, outside the nucleus.
The investigators note that similar retention of p27 in the cytoplasm has been reported in other cancers, including thyroid cancers, esophageal cancer, and colorectal cancers. Arteaga and coworkers are currently developing antibodies that specifically recognize p27 phosphorylated by Akt to use them in breast cancer clinical trials.
Arteaga’s collaborators in this report included Incheol Shin, F. Michael Yakes, and Andrei V. Bakin of Vanderbilt’s Department of Medicine; Nah-Young Shin of Vanderbilt’s Department of Cell Biology; and Federico Rojo and Jose Baselga of the Oncology Service at Vall d’Hebron University Hospital in Barcelona, Spain.
Drs. Rojo and Baselga, at Barcelona, analyzed 100 invasive breast cancers. Consistent with the molecular biology studies performed at Vanderbilt, p27 was exclusively nuclear in tumors in which activated Akt was undetectable. On the other hand, in tumors with detectable active Akt, p27 was localized in the tumor cell cytosol. Cytosolic p27 correlated with higher tumor grade suggesting that this finding might have prognostic implications in human breast cancer. “I can not praise enough the contribution of Drs. Rojo and Baselga to our studies. Their analysis in the breast cancer cohort from Barcelona provides the human cancer relevance to our molecular studies on p27,” Arteaga said.