Inhibition of cathepsin proteases inhibits tumor formation in transgenic mice

05/11/04




A new research study provides evidence that inhibition of cathepsin cysteine proteases may be a viable strategy for treatment of human cancers. Cathepsins are shown to be involved in multiple stages of tumor development in transgenic mouse models of cancer, and pharmacological inhibition of cathepsins impairs tumor growth and progression. The research is published in the May issue of Cancer Cell.

Molecules known as proteases have long been linked with cancer in humans, and the cathepsins are known to be associated with some human malignancies. However, a specific role for cysteine cathepsin proteases in tumor progression has not been examined in detail, and cathepsins as a potential therapeutic target for treatment of cancer have not been previously reported. Dr. Matthew Bogyo from Stanford Medical School and Dr. Douglas Hanahan from the University of California at San Francisco and colleagues demonstrated that cathepsins are elevated in tumors that form in a mouse model of a rare form of pancreatic cancer and a mouse model of cervical cancer. Using specialized chemical reporters that detected enzymatic activity of cathepsins, the researchers revealed that elevated cathepsins activity in tumors was correlated with the formation of tumor blood vessels (angiogenesis), tumor growth, and invasion into normal tissue in these tumor-bearing mice.

Furthermore, treatment of the cancer-prone mice with a pharmacological inhibitor of cysteine cathepsin activity disrupted both early and late stages of tumor development. The effective dose of the inhibitor was not toxic to normal cells, suggesting that it may be a potential candidate for use in the treatment of human cancers.

These results point to cathepsins as a viable target for future anticancer therapeutics. According to Dr. Hanahan, "It is reasonable to suggest that cathepsin inhibitors may show combinatorial benefits with other targeted (and traditional) therapies, which could be revealed in preclinical trials involving this and other mouse models of human cancer."

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