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.
Dr. Joyce and colleagues found that E-cadherin (a known inhibitor of tumor invasion) is a target substrate of cathepsins B, L and S - but not cathepsin C. Their evidence suggests that cathepsins B, L and S promote pancreatic tumor invasion by cleaving, and thereby inactivating, E-cadherin. Interestingly, the researchers also found elevated levels of cathepsins B and L in some human pancreatic tumor samples.
Dr. Joyce explains that "Using the powerful approach of mouse genetics, we have been able to identify distinct, stage-specific roles for members of the cysteine cathepsin family. These data should provide insight into both the stage in cancer development in which to target cathepsins, as well as the individual family members to target. Our functional studies in mice and our analysis of human pancreatic tumors suggest that a selective inhibitor of cathepsins B and L could have therapeutic value against invasive carcinomas."