Molecular and pharmacological validation of Cathepsin S as a novel target in cancer treatment

Malignant cancer is hallmarked by the ability of the tumour to invade its normal surrounding tissue thus permitting its development and spread, frequently to distal sites/organs. The development of these secondary tumours is normally the cause of mortality in the patient. This proposal aims to evaluate the potential for the therapeutic blocking of a destructive enzyme, cathepsin S, in the development and spread of aggressive tumours. Over-produced by tumour and tumour associated cells, the inhibition of this protease may in the future prove useful in combination with chemotherapeutic agents to not only kill the cancer cells but to prevent the spread and seeding of these secondary metastases.

The cysteine protease, cathepsin s, has been implicated in the promotion of the invasive and angiogenic phenotypes of aggressive tumours. Normally found in lysosomes of cells with a restricted tissue expression, cathepsin S has been implicated in the progression of aggressive metastatic tumours. Immunohisto- and biochemical characterization of tumour biopsies has revealed expression and secretion of CatS, where it is thought to mediate remodelling of the extracellular matrix, promoting growth and spread of the tumour and tumour-associated cells. The aim of this work is to validate the targeting of cathepsin S as an anti-tumour therapeutic target; and to evaluate therapeutic inhibition of the enzyme in models of primary tumours and metastases. This investigation will involve the application of in vivo synengenic murine studies to examine both tumour development with stratified cathespin S depletion and the evaluation of a novel experimental therapeutic towards cathepsin S.