Targeting Mesotrypsin-Induced Prostate Cancer Progression

In prostate cancer, as in most other cancers, what kills patients is metastasis, the spread of cancer from the primary tumor. Tumor cells must acquire the capacity to break down tissue structure in order to escape the physical barriers that contain a growing primary tumor, to enter the vascular system, to exit the vascular system at a distant point, and to colonize a distant organ. Tumor cells accomplish this in part through the production of proteases, molecules that can degrade the protein component of tissues. A protease that is specifically produced by tumors to facilitate the spread of cancer could be a very good target for a new cancer drug, as inhibition of a tumor-specific protease might effectively prevent the invasive processes necessary for a cancer to spread.

We have recently made an exciting discovery that provides key new insights towards understanding prostate cancer spread, and also indicates pathways to development of new prostate cancer therapies: we have found that a protease called mesotrypsin, which is related to proteases that work in the digestive system to digest our food, is inappropriately produced by prostate tumors. Our preliminary data show that the tumors of men with advanced, metastatic prostate cancer were most likely to produce high levels of mesotrypsin. Additionally, men with localized prostate tumors producing high levels of mesotrypsin were more likely to experience cancer relapse after prostatectomy. When we studied prostate cancer cells in the laboratory, we found that exposing them to mesotrypsin caused them to behave more aggressively and invasively. Our studies suggest that mesotrypsin might be a good therapeutic target; that is, by blocking mesotrypsin, we might be able to block or inhibit the spread of prostate cancer.

A number of questions must be considered in designing a therapeutic strategy to target a protease: (1) Does the protease in question have any important or essential biological functions in health? In considering whether mesotrypsin might make a good therapeutic target, it is a definite advantage that mesotrypsin has no known essential physiological functions; in fact, most organisms (including most other mammals) do not even have a gene to make mesotrypsin, so blocking its function is unlikely to lead to problematic side effects. (2) Is the protease in question truly critical to the spread of cancer? We do not yet know the answer to this question, which we will address with the experiments proposed in our Specific Aim 1. These experiments will tell us how mesotrypsin makes prostate cells become more invasive, what is the extent of its influence on prostate cancer invasion and metastasis in animals, and at which stage it exerts its effect. (3) Can the protease be effectively blocked without interfering with other, possibly similar proteases with important biological functions in health? Our preliminary data have given us some very good indications that mesotrypsin is different enough from its relatives to allow us to design a drug that will block mesotrypsin without interfering in the functions of 'good' proteases. In Specific Aim 2, we propose to use cutting-edge technologies to develop mesotrypsin-inhibiting drugs based on naturally occurring human proteins.

As with the development of any entirely novel therapeutic, the process of translating our discovery to the clinic is likely to require several years of testing in animals, recruitment of a pharmaceutical company to bring the drug to market, an average of 5 years of clinical testing, and 1-2 years for government approval. However, the engineered mesotrypsin inhibitors that we generate will have several advantages that may enhance their probability of clinical development in a timely fashion. Because they are based on natural human proteins, they are likely to be well-tolerated, with reduced potential for adverse side effects or immune responses. Furthermore, as protein therapeutics, they offer a slightly accelerated timeline for clinical development and approval, as well as far-reaching patent protection, both significant advantages in attracting a pharmaceutical company willing to invest the resources to bring these new drugs to the clinic. For patients with prostate cancer, the potential impact of a well-tolerated and highly selective mesotrypsin inhibitor might be as an effective new treatment option for blocking prostate cancer progression in patients with localized disease but poor prognosis, such as those for whom lymph node-positive disease has been detected.