Matrix Metalloproteinases as Biomarkers and Treatment Targets in Mesothelioma: A Systematic Review

Metalloproteinases (MMPs) have an important role in tissue remodeling and have been shown to have an effect on tumor progression, invasion, metastasis formation, and apoptosis in several tumors, including mesothelioma. Mesothelioma is a rare tumor arising from pleura and peritoneum and is frequently associated with asbestos exposure. We have performed a systematic search of PubMed.gov and ClinicalTrials.gov databases to retrieve and review three groups of studies: studies of MMPs expression in tumor tissue or body fluids in patients with mesothelioma, studies of MMPs genetic variability, and studies of MMPs as potential novel drug targets in mesothelioma. Several studies of MMPs in mesothelioma tissues reported a link between higher expression levels of commonly studied MMPs and clinical parameters, such as overall survival. Fewer studies have investigated genetic variability of MMP genes. Nevertheless, these studies suggested that certain genetic variants in MMP genes can have either protective or tumor-promoting effects on mesothelioma patients. MMPs have been also reported as novel drug targets, but so far no clinical trials of MMP inhibitors are registered in mesothelioma. In conclusion, MMPs play an important role in mesothelioma, but further studies are needed to elucidate the potentials of MMPs as biomarkers and drug targets in mesothelioma.

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Novel drug targets in 2019

Nature Reviews Drug Discovery ◽

10.1038/d41573-020-00052-w ◽

2020 ◽

Vol 19 (5) ◽

pp. 300-300 ◽

Cited By ~ 1

Author(s):

Sorin Avram ◽

Liliana Halip ◽

Ramona Curpan ◽

Tudor I. Oprea

Keyword(s):

Drug Targets ◽

Novel Drug ◽

Novel Drug Targets

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Cyclic Nucleotide Signaling Pathways in Apicomplexan Parasites Provide a Valuable Source for Novel Drug Targets

10.33696/signaling.1.005 ◽

2020 ◽

Keyword(s):

Signaling Pathways ◽

Cyclic Nucleotide ◽

Drug Targets ◽

Valuable Source ◽

Apicomplexan Parasites ◽

Nucleotide Signaling ◽

Novel Drug ◽

Novel Drug Targets

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Identification and Validation of Novel Drug Targets in Tuberculosis

Current Pharmaceutical Design ◽

10.2174/1381612043383223 ◽

2004 ◽

Vol 10 (26) ◽

pp. 3185-3194 ◽

Cited By ~ 35

Author(s):

K. Duncan

Keyword(s):

Drug Targets ◽

Novel Drug ◽

Novel Drug Targets

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Structural Systems Pharmacology: A New Frontier in Discovering Novel Drug Targets

Current Drug Targets ◽

10.2174/1389450111314090003 ◽

2013 ◽

Vol 14 (9) ◽

pp. 952-958 ◽

Cited By ~ 5

Author(s):

Hepan Tan ◽

Xiaoxia Ge ◽

Lei Xie

Keyword(s):

Drug Targets ◽

Structural Systems ◽

Systems Pharmacology ◽

New Frontier ◽

Novel Drug ◽

Novel Drug Targets

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Identification of Polo-like kinases as potential novel drug targets for influenza A virus

Scientific Reports ◽

10.1038/s41598-017-08942-7 ◽

2017 ◽

Vol 7 (1) ◽

Cited By ~ 7

Author(s):

Marie O. Pohl ◽

Jessica von Recum-Knepper ◽

Ariel Rodriguez-Frandsen ◽

Caroline Lanz ◽

Emilio Yángüez ◽

...

Keyword(s):

Influenza A Virus ◽

Drug Targets ◽

Influenza A ◽

Novel Drug ◽

Novel Drug Targets

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Utilizing Functional Genomics Screening to Identify Potentially Novel Drug Targets in Cancer Cell Spheroid Cultures

Journal of Visualized Experiments ◽

10.3791/54738 ◽

2016 ◽

Cited By ~ 4

Author(s):

Eamonn Morrison ◽

Patty Wai ◽

Andri Leonidou ◽

Philip Bland ◽

Saira Khalique ◽

...

Keyword(s):

Functional Genomics ◽

Cancer Cell ◽

Drug Targets ◽

Cell Spheroid ◽

Novel Drug ◽

Novel Drug Targets

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Multi-omics data integration reveals novel drug targets in hepatocellular carcinoma

BMC Genomics ◽

10.1186/s12864-021-07876-9 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Christos Dimitrakopoulos ◽

Sravanth Kumar Hindupur ◽

Marco Colombi ◽

Dritan Liko ◽

Charlotte K. Y. Ng ◽

...

Keyword(s):

Hepatocellular Carcinoma ◽

Drug Targets ◽

Mtor Signaling ◽

Omics Data ◽

Genetic Changes ◽

Genetic Aberrations ◽

Functional Consequences ◽

Novel Drug ◽

Novel Drug Targets ◽

Omics Data Integration

Abstract Background Genetic aberrations in hepatocellular carcinoma (HCC) are well known, but the functional consequences of such aberrations remain poorly understood. Results Here, we explored the effect of defined genetic changes on the transcriptome, proteome and phosphoproteome in twelve tumors from an mTOR-driven hepatocellular carcinoma mouse model. Using Network-based Integration of multi-omiCS data (NetICS), we detected 74 ‘mediators’ that relay via molecular interactions the effects of genetic and miRNA expression changes. The detected mediators account for the effects of oncogenic mTOR signaling on the transcriptome, proteome and phosphoproteome. We confirmed the dysregulation of the mediators YAP1, GRB2, SIRT1, HDAC4 and LIS1 in human HCC. Conclusions This study suggests that targeting pathways such as YAP1 or GRB2 signaling and pathways regulating global histone acetylation could be beneficial in treating HCC with hyperactive mTOR signaling.

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Abstract P283: CCL5 Acts As A Vasoconstrictor On Penetrating Arterioles In The Cerebral Circulation By Enhancing 20-HETE Activity

Hypertension ◽

10.1161/hyp.78.suppl_1.p283 ◽

2021 ◽

Vol 78 (Suppl_1) ◽

Author(s):

Reece F Crumpler ◽

Huawei Zhang ◽

Xing Fang ◽

Shaoxun Wang ◽

Baoying Zheng ◽

...

Keyword(s):

Drug Targets ◽

Perfusion Pressure ◽

Synthesis Inhibitor ◽

Atherosclerosis Risk In Communities ◽

Cyp Enzymes ◽

Sd Rats ◽

Sodium Regulation ◽

Novel Drug ◽

The Brain ◽

Novel Drug Targets

20-HETE is synthesized from arachidonic acid by cytochrome P450 (CYP) enzymes 4A and 4F. Inactivating mutations in the CYP enzymes that produce 20-HETE are associated with hypertension and stroke in man. We previously revealed that inactivating variants of CYP4A/F enzymes are associated with dementia in the Atherosclerosis Risk in Communities Neurocognitive Study (ARIC-NS) population. 20-HETE is involved with sodium regulation in the kidney and is a powerful vasoconstrictor. It was recently discovered that CCL5 and 20-HETE share the same receptor, GPR75. We previously found that 20-HETE constricts and augments the myogenic response (MR) of the middle cerebral artery (MCA) and renal afferent arteriole. However, whether CCL5 has any effect on penetrating arterioles (PAs) and interacts with 20-HETE is unknown. We found that GPR75 is expressed in PAs and pericytes in the brain. CYP4A is also expressed in pericytes and is inversely proportional to levels of GPR75 in the brain. In the present study, we found that 20-HETE contributes to the basal myogenic tone of PAs in SD rats. Administration of HET0016, a 20-HETE synthesis inhibitor, dilated the PA by 34 ± 3% (n = 6) under 10 mmHg perfusion pressure. Administration of WIT003, a 20-HETE agonist, constricted the vessel by 23 ± 4% (n = 6) under the same perfusion pressure. We found that CCL5 also reduced PA diameter by 20 ± 4% (n = 7) in SD rats under 10 mmHg perfusion pressure. Moreover, we compared the response to CCL5 in SS rats that are 20-HETE deficient and SS.CYP4A1 transgenic rats in which 20-HETE production is restored. PAs isolated from SS rats treated with 0.1 nM CCL5 constricted by 9 ± 5% (n = 6) while those treated with 10 nM constricted by 12 ± 3% (n = 6). CCL5 had a greater response in PAs from the SS.CYP4A1 strain, and the diameter of the PAs constricted by 14 ± 2% (n = 5) and 24 ± 5% (n = 5) in response to 0.1 and 10 nM CCL5, respectively. These results demonstrate that CCL5 has a direct effect on PAs similar to 20-HETE that acts via the GPR75 receptor. However, further study is needed to determine how CCL5 and 20-HETE interact to promote vasoconstriction. These studies would help further understand the involvement of 20-HETE in disease and potentially identify novel drug targets.

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