Kallikrein-related peptidases targeted therapies in prostate cancer: perspectives and challenges

Cereda, Vittore; Formica, Vincenzo; Menghi, Antonello; Pellicori, Stefania; Roselli, Mario

doi:10.1517/13543784.2015.1035708

Cited by 10 publications

(6 citation statements)

References 94 publications

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“…Similarly, a KLK13 specific mAb inhibited the activity of this kallikrein, suggesting that it might have therapeutic application in the treatment of ovarian cancer patients [30]. The overall stability, good tolerance, and long-term inhibitory activity encourage further investigations into the development of specific antibodies as potential therapeutic agents in the treatment of pathologies related to excessive kallikrein activity [31]. …”

Section: Kallikreins As Proteases: Basic Informationmentioning

confidence: 99%

Kallikreins – The melting pot of activity and function

et al. 2016

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The human tissue kallikrein and kallikrein-related peptidases (KLKs), encoded by the largest contiguous cluster of protease genes in the human genome, are secreted serine proteases with diverse expression patterns and physiological roles. Because of the broad spectrum of processes that are modulated by kallikreins, these proteases are the subject of extensive investigations. This review brings together basic information about the biochemical properties affecting enzymatic activity, with highlights on post-translational modifications, especially glycosylation. Additionally, we present the current state of knowledge regarding the physiological functions of KLKs in major human organs and outline recent discoveries pertinent to the involvement of kallikreins in cell signaling and in viral infections. Despite the current depth of knowledge of these enzymes, many questions regarding the roles of kallikreins in health and disease remain unanswered.

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Section: Kallikreins As Proteases: Basic Informationmentioning

confidence: 99%

Kallikreins – The melting pot of activity and function

et al. 2016

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“…It was previously reported that kininogen 1, the human homolog, is elevated in the urine of men diagnosed with PCa [ 21 ]. This protein can activate the mitogen-activated protein kinase (MAPK) pathway and promote the proliferation and survival of PCa cells [ 30 ]. EGF is also involved in the regulation of prostate growth and function, and its expression is increased in early and localized PCa; however, in our study, we observed a decrease in its levels in the urine of PCa2 animals and in animals with score 2 lesions, which may be explained by the stage of prostate carcinogenesis [ 31 , 32 ].…”

Section: Discussionmentioning

confidence: 99%

Tracking Prostate Carcinogenesis over Time through Urine Proteome Profiling in an Animal Model: An Exploratory Approach

Moreira‐Pais

Nogueira-Ferreira

Reis

et al. 2022

IJMS

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Prostate cancer (PCa) is one of the most lethal diseases in men, which justifies the search for new diagnostic tools. The aim of the present study was to gain new insights into the progression of prostate carcinogenesis by analyzing the urine proteome. To this end, urine from healthy animals and animals with prostate adenocarcinoma was analyzed at two time points: 27 and 54 weeks. After 54 weeks, the incidence of pre-neoplastic and neoplastic lesions in the PCa animals was 100%. GeLC-MS/MS and subsequent bioinformatics analyses revealed several proteins involved in prostate carcinogenesis. Increased levels of retinol-binding protein 4 and decreased levels of cadherin-2 appear to be characteristic of early stages of the disease, whereas increased levels of enolase-1 and T-kininogen 2 and decreased levels of isocitrate dehydrogenase 2 describe more advanced stages. With increasing age, urinary levels of clusterin and corticosteroid-binding globulin increased and neprilysin levels decreased, all of which appear to play a role in prostate hyperplasia or carcinogenesis. The present exploratory analysis can be considered as a starting point for studies targeting specific human urine proteins for early detection of age-related maladaptive changes in the prostate that may lead to cancer.

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“…Based on our findings, we anticipate that direct/indirect targeting of KLK by selective synthetic KLK inhibitors and modulators will be an effective therapeutic strategy that can be combined with standard chemo-radiotherapy [ 38 ] or immune checkpoint inhibitors, which is especially promising considering the important role of KLKs in the immune response. As in the case of prostate-specific membrane antigen targeted by antitumor vaccines [ 39 ], KLK serine proteases are potential targets for immunotherapy.…”

Section: Discussionmentioning

confidence: 99%

Kallikrein 5 overexpression is associated with poor prognosis in uterine cervical cancer

Chang

Kim

et al. 2020

J Gynecol Oncol

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Objective Kallikrein 5 (KLK5), which is frequently observed in normal cervico-vaginal fluid, is known to be related to prognosis in several solid tumors. We investigated the prognostic significance of KLK5 in uterine cervical cancer using tumor tissue microarray and immunohistochemistry staining. Methods We analyzed samples of 165 patients with uterine cervical cancer who received definitive radiation therapy between 2004 and 2012. We divided patients into two groups stratified by their KLK5 activity by immunohistochemistry staining: negative/weak (0–1+) (n=120 patients) and moderate/strong (2–3+) group (n=45 patients). Patient and tumor characteristics, patterns of failure, and survival outcomes were compared. Univariable and multivariable analyses were performed to identify prognostic factors. Results Patients with KLK5 2–3+ were younger (median: 52 vs. 60 years) and had frequent paraaortic lymph node involvement (40.0% vs. 18.3%) than those with KLK5 0–1+. With a median follow-up of 60.8 (interquartile range, 47.5–77.9) months, patients with KLK5 2–3+ had inferior 5-year locoregional recurrence-free survival and distant metastasis-free survival of 61.7% (vs. 77.5% in KLK5 0–1+ group) and 59.4% (vs. 72.8% in the KLK5 0–1+ group), respectively (all p<0.05). KLK5 2–3+ expression retained its significance after adjusting for other well-known prognostic factors of tumor size and stage in multivariable analysis. Conclusions KLK5 overexpression is associated with the aggressiveness of cervical cancer and may underlie the diminished response to conventional treatments. Therefore, KLK5 could be a reliable prognostic factor in cervical cancer.

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Kallikrein-related peptidases targeted therapies in prostate cancer: perspectives and challenges

Abstract: Targeting KLK expression and/or activity could be a promising direction in prostate cancer treatment. Future human clinical trials will help us to evaluate the real benefits, toxicities and the consequent optimal use of KLK-targeted drugs, as mono-therapy or in combination regimens.

Cited by 10 publications

References 94 publications

Kallikreins – The melting pot of activity and function

Kallikreins – The melting pot of activity and function

Tracking Prostate Carcinogenesis over Time through Urine Proteome Profiling in an Animal Model: An Exploratory Approach

Kallikrein 5 overexpression is associated with poor prognosis in uterine cervical cancer

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