Title: Kunitz-Based Protease Inhibitors of Mesotrysin as Antimetastatic Cancer Therapies
Case Number: 2010-173
Innovators: Evette S. Radisky Ph.D.; Mohd A. Salameh Ph.D.
Description
Mesotrypsin Inhibitors for the Treatment of Multiple Metastatic Cancers
Metastatic tumors including metastatic prostate cancer are often refractory to current therapies. Improved treatments are needed that inhibit the metastatic potential of tumors. Mesotrypsin is an isoform of trypsin that is upregulated in advanced prostate cancer and other cancers including non-small cell lung cancer, colon cancer, and breast cancer. Mesotrypsin expression is predictive of prostate cancer recurrence and promotes malignant morphology, invasion, and metastasis of prostate cancer in 3D culture assays and mice. Reducing mesotrypsin expression in human prostate cancer tumors implanted into mice dramatically reduces tumor metastasis in the animals. Mayo Clinic researchers have identified natural polypeptide inhibitors of the Kunitz family as leads for the development of mesotrypsin inhibitors. Protein crystallography and enzyme kinetics studies of Kunitz family members have been conducted to characterize and optimize inhibitors of mesotrypsin, and prototype inhibitors have been identified with superior mesotrypsin binding and proteolytic stability. These inhibitors block prostate cancer cell invasion and malignant growth of breast cancer cells in 3D culture.
Application
Treatment of metastatic cancers including prostate, breast, colon, and lung.
Stage of Development
Optimized polypeptide inhibitors of mesotrypsin have been developed that block cell invasion and malignant growth of prostate and breast cancer cells in cell culture systems. Mutation studies are ongoing to further optimize polypeptide inhibitors, and mutated polypeptides have been identified that are more effective inhibitors of mesotrypsin than wild-type polypeptides.
References
Salameh et al. Determinants of affinity and proteolytic stability in interactions of Kunitz family protease inhibitors with mesotrypsin. J Biol Chem 2010;285(47):36884-96.
Hockla et al. Mesotrypsin promotes malignant growth of breast cancer cells through shedding of CD109. Breast Cancer Res Treat 2010;124(1):27-38.
Salameh et al. The amyloid precursor protein/protease nexin 2 Kunitz inhibitor domain is a highly specific substrate of mesotrypsin. J Biol Chem 2010;285(3):1939-49.
Patent Status: Non-Provisional
Licensing Contact
Manu S. Nair, 507-266-0558
nair.manu@mayo.edu
Categories
Technology Area/Oncology - Cancer
Technology Area/Biologics
Technology Category/Therapeutic
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