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Investigational cancer drug targets critical proteins

Medical College of Georgia at Augusta University

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IMAGE: Dr. Yonghua Yang, postdoctoral fellow in molecular oncology in the laboratory of Dr. Kapil Bhalla, director of the Medical College of Georgia Cancer Center. view more

Credit: Medical College of Georgia

A drug under study to treat various cancers selectively kills cancer cells because of its affinity for a modified version of a critical heat shock protein they contain, researchers have found.

They found in cancer a modified version of heat shock protein 90, or hsp90, which like most heat shock proteins, promotes cell survival.

They then showed that in breast cancer and leukemia, this modification, called acetylation, confers a strong attraction to investigational drug 17-AAG, says Dr. Yonghua Yang, postdoctoral fellow in molecular oncology in the laboratory of Dr. Kapil Bhalla, director of the Medical College of Georgia Cancer Center.

"17-AAG blocks the activity of hsp90, which normally binds with ATP, an energy source for cells," says Dr. Yang, who received a training award to present his research at the American Association for Cancer Research Annual Meeting April 14-18 in Los Angeles.

An unfortunate side effect is that 17-AAG also immediately induces hsp70, which can compensate for the cell-supporting activity of hsp90, says Dr. Yang, noting that like hsp90, hsp70 presents a modified form in cancer.

The net effect is that while the drug ably finds its target, to maximize effectiveness it may need to be modified or used in conjunction with another drug to also block hsp70, Dr. Yang says. MCG researchers are in discussions with Novartis and Kosan Pharmaceuticals about how to make one or the other happen.

17-AAG doesn't seem to care much for normal hsp90 or hsp70 in healthy individuals, he says. Modifications in cancer result from environmental triggers, including stress and eating a lot of oxidated foods, such as foods fried at high temperatures or stored for a long time - more good reasons to relax and eat a well- balanced diet, Dr. Yang says.

The MCG researchers are now looking at the relationship between the modified hsp90 and breast cancer metastasis and developing antibodies that target hsp90.

Heat shock proteins are called molecular chaperones because of their caretaker role. They activate genes that ultimately make proteins, move proteins around cells and fold them into the proper shape so they'll have the proper function. Chaperones even help proteins group properly and discard old proteins.

Misfolding of proteins, for example, can cause cancer. Molecular chaperones are highly expressed in human cancer and seem resistant to radiation therapy and chemotherapy, according to Dr. Bhalla.

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