ADAM17 inhibiittorit kehittelyssä (2018)

https://www.researchgate.net/publication/320828392_Recent_Advances_in_ADAM17_Research_A_Promising_Target_for_Cancer_and_Inflammation Marcia Moss:
Abstract
Since its discovery, ADAM17, also known as TNF α converting enzyme or TACE, is now known to process over 80 different substrates. Many of these substrates are mediators of cancer and inflammation. The field of ADAM metalloproteinases is at a crossroad with many of the new potential therapeutic agents for ADAM17 advancing into the clinic. Researchers have now developed potential drugs for ADAM17 that are selective and do not have the side effects which were seen in earlier chemical entities that targeted this enzyme. ADAM17 inhibitors have broad therapeutic potential, with properties ranging from tumor immunosurveillance and overcoming drug and radiation resistance in cancer, as treatments for cardiac hypertrophy and inflammatory conditions such as inflammatory bowel disease and rheumatoid arthritis. This review focuses on substrates and inhibitors identified more recently for ADAM17 and their role in cancer and inflammation.

cGAS- cGAMP- STING signaalitiestä ja sen merkityksestä dsDNA materian sensorina

http://jem.rupress.org/content/215/5/1287



 http://jem.rupress.org/content/jem/215/5/1287/F2.medium.jpg
 

Antisheddaasi strategia esim ADAM10/ADAM17 inhibiittorit ?

Cancer Biol Ther. 2016 Aug; 17(8): 870–880.

Published online 2016 Apr 26. doi: 10.1080/15384047.2016.1177684

PMCID: PMC5004698

PMID: 27115328

The ADAMs family of proteases as targets for the treatment of cancer

Maeve Mullooly,^a,b Patricia M. McGowan,^b,c John Crown,^d and Michael J. Duffy^b,e

Author information Article notes Copyright and License information Disclaimer

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5004698/

Conclusion

Although several different ADAMs have been implicated in cancer development and evolution, the strongest evidence is found with ADAM17. Indeed, as mentioned above, there is substantial preclinical evidence supporting the involvement of this ADAM in cancer development or metastasis. These findings have encouraged the development of multiple inhibitors against ADAM17 for their potential use in the treatment of cancer. However, because of the multiplicity of actions mediated by ADAM17, it might be expected that long-term blockage of its protease activity would cause toxicity such as depressed immunity and an increased risk of infection. Such toxicity however, did not appear to emerge in the short-term animal model studies reported to date. Furthermore with the only ADAM10/17 inhibitor so far investigated in clinical trials, i.e., INCB7839 in phase I/II trials, no major toxicity was reported.^40,41 Indeed, INCB7839, in contrast to the early MMP inhibitors investigated for potential anti-cancer activity, did not cause musculoskeletal side effects.^35,36 To-date, monoclonal antibodies against ADAM17 do not appear to have undergone studies in clinical trials. These biological inhibitors however, might be expected to exhibit more specific targeting than low molecular weight compounds and thus have less toxicity. The time may now be ready to test ADAM17 monoclonal antibodies in clinical trials.

Semaforiineista ja niiden pilkkoutumisesta. ADAMTS1

Tässä lähdeartikkelissa maintiaan ADAMTS1 pilkkomassa esiin  SEMA3C.stä   N-erminaalista fragmenttia, jota erittyy  ECM.stä ja  joka vaikuttaa  tuumorin migroitumista ja  etäkasvua.  ADAMTS1 on jo aiemmin tunnettu  mm syöpäkakeksiassa ilmenevänä  metalloproteinaasina.
Metalloproteinaaseja,   niiden   valtavaa vaikutusta   ei vielä pystytä hallitsemaan lääkkeellisesti.


https://www.dovepress.com/impact-of-semaphorin-expression-on-prognostic-characteristics-in-breas-peer-reviewed-fulltext-article-BCTT
Ramesh Butti, Totakura VS Kumar, Ramakrishna Nimma, Gopal C Kundu

Laboratory of Tumor Biology, Angiogenesis and Nanomedicine Research, National Centre for Cell Science, Savitribai Phule Pune University, Pune, India

Abstract: Breast cancer is one of the major causes of cancer-related deaths among women worldwide. Aberrant regulation of various growth factors, cytokines, and other proteins and their receptors in cancer cells drives the activation of various oncogenic signaling pathways that lead to cancer progression. Semaphorins are a class of proteins which are differentially expressed in various types of cancer including breast cancer. Earlier, these proteins were known to have a major function in the nerve cell adhesion, migration, and development of the central nervous system. However, their role in the regulation of several aspects of tumor progression has eventually emerged. There are over 30 genes encoding the semaphorins, which are divided into eight subclasses. It has been reported that some members of semaphorin classes are antiangiogenic and antimetastatic in nature, whereas others act as proangiogenic and prometastatic genes. Because of their differential expression and role in angiogenesis and metastasis, semaphorins emerged as one of the important prognostic factors for appraising breast cancer progression.

Keywords: breast cancer, tumor microenvironment, semaphorins, plexins, neuropilins, cancer stem-like cells, prognostic factor, angiogenesis, metastasis, epithelial to mesenchymal transition, vascular endothelial growth factor

• "....The other members of class 3 semaphorins, such as Sema3C and Sema3E, are overexpressed in breast cancer cells and exhibit tumor-promoting function. Zhu et al have shown that siRNA-mediated knockdown of Sema3C in breast cancer cells abolishes cell proliferation and migration.⁴⁹ Interestingly, the p65-Sema3C fragment that is generated from cleavage of full-length Sema3C by FPPC shows tumor-promoting role. Full-length Sema3C shows inhibitory effect on lymphangiogenesis and metastasis in mice breast tumor xenografts (Figure 2).⁵⁰ Nonetheless, the metalloprotease ADAMTS1 induces Sema3C cleavage from ECM and converts it to a soluble form, so that it diffuses and promotes tumor cell migration.⁵¹ The role of Sema3C in regulation of tumor progression also depends on the type and nature of cancers. For example, Sema3C promotes pancreatic cancer progression through ERK1/2 signaling pathway.⁵² However, the molecular mechanism by which Sema3C promotes breast cancer progression is unclear.

. (Figure 1).²⁶ Semaphorins also harbor other distinctive protein domains such as basic charged C-terminal domain, thrombospondin repeats, and immunoglobulin (Ig)-like domains. Class 3 semaphorins are characterized by a conserved, basic charged domain at the C-terminal region and these are secreted semaphorins (Figure 1).¹⁰ Class 4–7 semaphorins are cell membrane-anchored proteins that are characterized by their distinct structural elements. Thrombospondin repeats are present in case of class 5 semaphorins, whereas a glycophosphatidylinositol anchor is present in class 7 semaphorins (Figure 1). Membrane-anchored semaphorins can be further processed into soluble forms through the proteolytic cleavage at a specific site as in the case of class 4 and 7 semaphorins by ADAMTS1 and furin-like proprotein convertase (FPPC; Figure 1).^27,28

Figure 2 Semaphorin signaling in breast cancer.

Notes: Sema3A interacts with NRP1 receptor to induce PTEN/FOXO 3a-dependent MelCAM expression, which, in turn, inhibits tumor growth and angiogenesis. Sema3B binds to NRP1 and induces apoptosis by inhibiting PI3K/Akt signaling. Full-length Sema3C interacts with NRP2 on the lymphatic endothelial cells in tumor and suppresses lymphangiogenesis and metastasis by inhibiting VEGF-C–dependent ERK1/2 and Akt signaling. Full-length Sema3C undergoes proteolytic cleavage by FPPC to form p65-Sema3C, which promotes cancer cell survival. Sema4D binds to plexin-B1 and activates ErbB2, which, in turn, phosphorylates plexin-B1. Phosphorylated plexin-B1 induces migration by activating RhoA GTPase. Cleaved p61-Sema3E binds to plexin-D1 to promote metastasis through ErbB2-dependent MAPK signaling. Sema3E binds to plexin-D1 to inhibit apoptosis by disrupting the interaction between plexin-D1 and NR4A, which is known to induce caspase-9–mediated apoptosis. Sema7A interacts with integrin β1 on the cancer cells to promote invasion. Tumor-derived Sema7A binds with integrin β1 on the macrophages to promote angiogenesis by producing CXCL2, CXCL1, and MMP-9.

Abbreviations: ERK1/2, extracellular signal-regulated kinases1/2; FPPC, furin-like proprotein convertase; MMP, matrix metalloproteinase; PTEN, phosphatase and tensin homolog; VEGFR, vascular endothelial growth factor receptor.

ADAMTS1 lisätietoa: pilkkoo semaforiinia SEMA3C ja edistää metastasoitumista

https://www.ncbi.nlm.nih.gov/pubmed/?term=ADAMTS1+%2C+semaphorins

J Biol Chem. 2010 Jan 22;285(4):2463-73. doi: 10.1074/jbc.M109.055129. Epub 2009 Nov 13.

The cleavage of semaphorin 3C induced by ADAMTS1 promotes cell migration.

Esselens C¹, Malapeira J, Colomé N, Casal C, Rodríguez-Manzaneque JC, Canals F, Arribas J.Abstract

 

Metastasoituminen on sekventiaalinen prosessi, jossa soluille salliutuu  siirtyminen primäärituumorista muualle ksvamaan. Metalloproteinaaseja on ja kauan pidetty avainkomponenteina metastaattisessa ohjelmoitumisessa, koska niillä on kykyä  pilkkoa monenlaisia 

solunulkoisia signaloivia ja  adhesoituvia molekyylejä. Kuitenkin joidenkin metalloproteinaasien kuten ADAMTS1:n  funktio ei ole  ollut aivan selvä ja se näyttää riippuvan  solumiljööstä ja/tai tuumorin etenemisen  vaiheesta. Tässä artikkelin työssä haluttiin luonnehtia ADAMTS1 metalloproteaasin  funktioita ja suoritettiin kaksi  alternatiivista proteomiin perustuvaa tutkimusta tunnistettaessa  metalloproteinaasin uusia substraatteja. Kummatkin tutkimukset osoittivat, että ADAMTS1:n yli-ilmeneminen johti SEMA3C- semaforiinin  vapautumiseen extrasellulaarisesta  matriksista.  Vaikka tiedetäänkin jo, että semaforiinit ovat  aksonin ohjauksen säätelijöitä, on myös kertyvää näyttöä siitä, että ne osallistunevat myös tuumorin etenemiseen. Tässä työssä osoitettiin, että ADAMTS1:n indusoima semaforiinin SEMA3C  pilkkoutuminen edisti rintasyöpäsolujen migroitumista. Tämä viittaa siihen,  että näiden molekyylien samanaikaisilmenemä tuumoreissa saattaa osaltaan vaikutata  metastaattiseen ohjelmoitumiseen. 

• Metastasis is a sequential process that allows cells to move from the primary tumor and grow elsewhere. Because of their ability to cleave a variety of extracellular signaling and adhesion molecules, metalloproteases have been long considered key components of the metastatic program. However, the function of certain metalloproteases, such as ADAMTS1, is not clear and seems to depend on the cellular environment and/or the stage of tumor progression. To characterize the function of ADAMTS1, we performed two alternative proteomic approaches, difference gel electrophoresis and stable isotope labeling by amino acids in cell culture, to identify novel substrates of the metalloprotease. Both techniques showed that overexpression of ADAMTS1 leads to the release of semaphorin 3C from the extracellular matrix. Although semaphorins are well known regulators of axon guidance, accumulating evidence shows that they may also participate in tumor progression. Here, we show that the cleavage of semaphorin 3C induced by ADAMTS1 promotes the migration of breast cancer cells, indicating that the co-expression of these molecules in tumors may contribute to the metastatic program.

PMID:

19915008

PMCID:

PMC2807303

DOI:

10.1074/jbc.M109.055129

[Indexed for MEDLINE]

Free PMC Article

Muistiin  26.2. 2019 

Semaphorin perhe, SEMA4D

A different approach to inhibit tumor angiogenesis with anti-Sema4D antibodies was presented by Maurice Zauderer (Vaccinex). Sema4D is a member of the semaphorin family of proteins first identified as mediators in axon guidance. Sema4D is involved in the regulation of several different physiological processes, one of which is endothelial and epithelial cell migration. It also enhances CD40-induced immune and inflammatory cell activation, inhibits neurite extension and axon regeneration, and promotes survival and differentiation of oligodendrocyte precursor cells. As a multifunctional target, Sema4D may be of therapeutic relevance in numerous indications, e.g., cancers, rheumatoid arthritis, multiple sclerosis. Results from mouse models suggest that Sema4D antibodies could indeed have wide applicability. For example, a mouse Sema4D-specific antibody, MAb67, was as efficient as the clinically validated anti-TNF therapy etanercept (Enbrel^®) in haltling disease progression in an established collagen-induced arthritis model. Besides reducing the inflammatory response, the anti-Sema4D antibody also inhibited bone erosion. This may be explained with recent findings that Sema4D mediates osteoclast-osteoblast communication. In addition, Sema4D inhibition was also effective in an EAE model, where the clinical score was reduced by 50% by anti-Sema4D antibody treatment initiated during the onset of the disease.
Due to the abundant Sema4D expression on T cells and to a lesser extent on B cells, monocytes and dendritic cells, Vaccinex chose an IgG4 isotype for their humanized anti-Sema4D antibody VX15/2503 to avoid immune cell depletion. VX15/2503 inhibits membrane-bound human Sema4D, as well as a soluble Sema4D that is generated from the membrane-bound form by ectodomain shedding. VS15/2503 was shown to block Sema4D-induced collapse of the actin cytoskeleton and apoptosis in oligodendrocyte precursor cells in vitro. It also neutralized Sema4D mediated inhibition of oligodendrocyte precursor cell maturation into myelin basic protein-producing cells and reverted the inhibition of remyelation following lysophosphatidyl choline induced injury in postnatal brain slice cultures in vitro, thus indicating possible applications in multiple sclerosis patients.

Cu-metalloproteiinit

https://www.sciencedirect.com/science/article/pii/B9780080453828001805