title: Targeting kallikrein-related peptidases in prostate cancer.
abstract: BACKGROUND
  Novel therapeutic compounds are needed for prostate cancer (CaP), given the limitations of already used drugs and the disease's mortality, often attributed to castrate resistance. Tissue kallikrein and kallikrein-related peptidases (KLKs) form a family of serine proteases aberrantly expressed and broadly implicated in human malignancies. In CaP, KLKs participate in the promotion of cell proliferation, extracellular matrix degradation, tumour cell invasion and metastasis.
  
  
  METHODS
  This review discusses the different ways of inhibiting, modulating and exploiting KLK activity and/or expression as emerging CaP therapeutics. KLKs are targeted by diverse naturally occurring substances, including proteinaceous inhibitors, low-molecular-weight peptides and Zn(2+). Synthetic KLK inhibitors include protein/peptide-based inhibitors and small molecules. A re-engineered serpin-based KLK inhibitor is under evaluation in first-in-human trials as a CaP therapeutic, whereas additional potent and selective KLK inhibitors with relevance to CaP have been synthesized. KLK3-activated pro-drugs have entered Phase I and Phase II clinical trials as therapeutics for prostate tumours. The KLK3-based PROSTVAC® vaccine is evaluated in Phase III clinical trials. Targeting KLK expression via RNA interference methods could represent another promising therapeutic approach for CaP.
  
  
  CONCLUSIONS
  Apart from their immense biomarker potential, KLKs also hold promise as the basis of novel CaP therapeutics.
authors.affiliation: University of Athens, Department of Biochemistry and Molecular Biology , Panepistimiopolis, Athens , Greece.
authors.forename: Konstantinos
authors.initials: K
authors.lastname: Mavridis
authors.forename: Margaritis
authors.initials: M
authors.lastname: Avgeris
authors.forename: Andreas
authors.initials: A
authors.lastname: Scorilas
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002986:Clinical Trials as Topic / Q000379:methods; D016503:Drug Delivery Systems / Q000379:methods / Q000639:trends*; D006801:Humans; D008297:Male; D010447:Peptide Hydrolases / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000201:enzymology; D034622:RNA Interference / Q000502:physiology; D020840:Tissue Kallikreins / Q000037:antagonists & inhibitors* / Q000096:biosynthesis*
chemical_list: D000970:Antineoplastic Agents; D010447:Peptide Hydrolases; D020840:Tissue Kallikreins