To date, there are strong clinical associations and growing experimental evidence for cysteine and aspartic cathepsin proteases contributing to cancer progression by promoting the invasive and metastatic phenotype of solid tumors, such as mammary carcinomas. Our work using constitutive or cell type-specific cathepsin deletion established that those proteases reshape the tumor-microenvironment and affect intracellular signaling pathways. However, less is known on cell invasion-phenotypes and changes in cell signaling when cathepsins are deleted in already established tumors. Although there have been successful studies on combination of cathepsin inhibition with conventional cytotoxic chemotherapy regimens, there is no information on combination of cathepsin inhibition with selective inhibition with oncogenic kinase signaling. Therefore, we will advance the project into preclinical treatment trials testing genetic cathepsin deletion or pharmacological inhibition of these proteases alone or in combination with targeted therapies for metastasizing breast cancer.
Specifically, the project will address the following aspects:
- Conditional deletion of cathepsin proteases in established cancers and cancer cells.
- Combined inhibition of the PI3-kinase/mTOR pathway and cathepsins in breast cancer cells.
- Concept validation in human breast cancer cell lines and xenograft studies.