| Summary: | Emerging evidence has implicated cathepsin S with a pathological role within cancer. As a result, there is a need for novel tools to help unravel the role(s) this protease plays in cancer. A number of reversible and selective cathepsin S inhibitor compounds were evaluated in vitro to determine selectivity and cell permeablility. Following this, the inhibitors were evaluated using pre-clinical cellular models of tumour invasion and angiogenesis. l6 was chosen as a lead compound and evaluated in vivo, where it abrogated tumour progression in a colorectal model. Increased cathepsin S expression has been observed in tumour cells via an unknown mechanism. Our group proposed increased cathepsin S expression via a mechanism of collateral copy-number amplification of neighbouring gene MCL-1. The relationship was evaluated using gene-microarray datasets, which revealed correlation between CTSS and MCL-1, and poor patient outcome. Utilising l6 and doxorubicin, a combinational therapy approach was carried out using a breast xenograft model. Individual treatment produced a reduction in tumour volume, proliferation and concomitant increase in apoptosis, however, no additional effect was observed in combination, likely to be as a result of cellular stress mechanisms. Increased cathepsin S expression has been shown in several cancers, however, has been sparsely reported upon with respect breast cancer. Cathepsin S expression in infiltrating and tumour cells of patient samples was evaluated by tissue microarray. High cathepsin S expression in the infiltrating cells was associated with poor outcome. Interestingly, high cathepsin S expression in the tumour cells was associated with triple-negative breast cancer patients, and futhermore associated with improved prognosis, suggesting a protective role for cathepsin S. In summary, this thesis describes advances in the development of new inhibitor compounds for the elucidation of cathepsin S biology and furthermore, expands the current understanding of cathepsin S as a biomarker in breast cancer.
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