Investigational Drug Capitalizes on Critical Proteins
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 17AAG, said Dr. Yonghua Yang, postdoctoral fellow in molecular oncology in the laboratory of Dr. Kapil Bhalla, director of the MCG Cancer Center.
The Feature Box 17-AAG blocks the activity of hsp90, which normally binds with ATP, an energy source for cells.
“17AAG blocks the activity of hsp90, which normally binds with ATP, an energy source for cells,” said Dr. Yang, who received a training award to present his research at the American Association for Cancer Research Annual Meeting April 1418 in Los Angeles.
An unfortunate side effect is that 17AAG also immediately induces hsp70, which can compensate for the cellsupporting activity of hsp90, said 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. MCG researchers are in discussions with Novartis and Kosan Pharmaceuticals about how to make one or the other happen.
17AAG doesn’t seem to care much for normal hsp90 or hsp70 in healthy individuals. 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 wellbalanced diet, Dr. Yang said.
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.
