PROT-RESIST SIGNED

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 Project objective

Distal site tumor metastasis is the leading cause of prostate- and pancreatic-cancer-related deaths; nevertheless, standard-of-care (SoC) treatments and other targeted therapies under development are based on their activity against the primary tumors rather than on their anti-metastatic activity. There is consequently an urgent medical need for new agents targeting the metastatic process. In prostate and pancreatic cancer models, the serine protease mesotrypsin promotes tumor invasion and metastasis, making it an attractive target for therapeutic intervention. In our ERC StG project, we used directed evolution to generate a novel prototype mesotrypsin inhibitor, designated APPI-3M, which is based on the human amyloid β-protein precursor Kunitz protease inhibitor domain (APPI) scaffold. This inhibitor has picomolar affinity, enhanced binding specificity and improved proteolytic resistance to mesotrypsin and exhibits high potency in cell-based and preclinical models of prostate cancer invasion and metastasis. In this PoC proposal, we propose to perform final lead optimization (particularly decreasing body clearance) of APPI-3M towards its commercialization for clinical translation as an antimetastatic therapeutic adjuvant, with the direct involvement in the planning stage of clinicians and other key opinion leaders in the field. The feedback of these experts is expected to confirm the need to address the problem of metastatic progression and to identify potential indications and therapeutic windows for the use of APPI-3M as a neoadjuvant in prostate and pancreatic cancers. This input will be translated into feasible preclinical studies to demonstrate the contribution of APPI-3M therapy to currently ongoing SoC protocols for prostate and pancreatic cancers. In parallel, we will carry out the in-depth market and IP analyses needed for the commercialization of the engineered protein for therapeutic applications.