In the March 1 issue, Drs. Johanna Joyce (MSKCC), Douglas Hanahan (UCSF) and colleagues lend new insight into how broad-spectrum cysteine cathepsin inhibitors combat pancreatic cancer, and provide new data to help refine the design of more precisely targeted anti-cathepsin therapies.
"These results may help guide the design of clinical trials aimed to assess cathepsin inhibitors as cancer therapies" said Dr. Joyce
Their paper will be made available online ahead of print at www.genesdev.org on 2/15.
In 2004, the research team found that pharmacological inhibition of all cysteine cathepsins effectively thwarted tumor progression in a mouse model of pancreatic islet cell cancer. In their current study, Dr. Joyce and colleagues provide mechanistic insight into the specific roles that individual cathepsins play in tumorigenesis, and why their inhibition suppresses cancer development.
To determine how the loss of individual cathepsin genes affects tumorigenesis, the researchers engineered the pancreatic cancer-prone mice to also lack one of four cathepsin genes: cathepsin B, C, L or S. They found that cathepsin B-, L-, or S-deficient transgenic mice displayed reduced tumor formation - but cathepsin C-deficient mice did not. Dr. Joyce and colleagues were then able to identify the stage-specific roles of cathepsins B, L and S in tumor development, as well as a key downstream target that mediates the tumorigenic roles of these three cathepsins.