ADAM proteases: Emerging role and targeting of the non-catalytic domains
Nayanendu Saha1, Dorothea Robev1, Juha P Himanen1
1Sloan-Kettering Institute for Cancer Research, 1275 York Avenue, New York, NY, 10065, USA.
Abstract:
ADAM proteases are multi domain transmembrane metalloproteases that cleave a range of cell surface proteins and activate signaling pathways implicated in tumor progression, including those mediated by Notch, EFGR, and the Eph receptors. Consequently, they have emerged as key therapeutic targets in the efforts to inhibit tumor initiation and progression. To that end, two main approaches have been taken to develop ADAM antagonists: (i) small molecule inhibitors, and (ii) monoclonal antibodies. In this mini-review we describe the distinct features of ADAM proteases, particularly of ADAM10 and ADAM17, their domain organization, conformational rearrangements, regulation, as well as their emerging importance as therapeutic targets in cancer. Further, we highlight an anti-ADAM10 monoclonal antibody that we have recently developed, which has shown significant promise in inhibiting Notch signaling and deterring growth of solid tumors in pre-clinical settings.
Insights
ADAM proteases, like ADAM10, are crucial in cancer progression. A new anti-ADAM10 antibody effectively inhibits Notch signaling and reduces solid tumor growth in preclinical models, offering a promising cancer therapy.
Area of Science:
- Biochemistry
- Molecular Biology
- Oncology
Background:
- ADAM proteases are transmembrane metalloproteases involved in cleaving cell surface proteins.
- These proteases activate signaling pathways, such as Notch, EGFR, and Eph receptors, which are implicated in tumor progression.
- ADAM proteases are recognized as significant therapeutic targets for inhibiting tumor initiation and progression.
Purpose of the Study:
- To review the distinct features, domain organization, regulation, and therapeutic importance of ADAM proteases, particularly ADAM10 and ADAM17, in cancer.
- To highlight a newly developed anti-ADAM10 monoclonal antibody and its preclinical efficacy.
Main Methods:
- Review of literature on ADAM proteases, focusing on ADAM10 and ADAM17.
- Description of ADAM protease domain organization and regulation.
- Presentation of preclinical data for a novel anti-ADAM10 monoclonal antibody.
Main Results:
- ADAM10 and ADAM17 play critical roles in cancer by modulating key signaling pathways.
- The developed anti-ADAM10 monoclonal antibody demonstrates significant promise.
- This antibody effectively inhibits Notch signaling and deters solid tumor growth in preclinical settings.
Conclusions:
- ADAM proteases are validated therapeutic targets in oncology.
- The novel anti-ADAM10 monoclonal antibody represents a promising strategy for cancer treatment by inhibiting tumor growth and progression.
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