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Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy

Nature Reviews Cancer volume 6, pages 227–239 (2006)Cite this article

Abstract

The matrix metalloproteinases (MMPs) mediate homeostasis of the extracellular environment. They have multiple signalling activities that are commonly altered during tumorigenesis and that might serve as intervention points for anticancer drugs. However, there are many criteria to consider in validating MMPs as drug targets and for the development of MMP inhibitors. The inhibition of some MMPs could have pro-tumorigenic effects (making them anti-targets), counterbalancing the benefits of target inhibition. These effects might partially account for the failure of MMP inhibitors in clinical trials. What are the major challenges in MMP target validation and MMP-inhibitor-drug development?

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Figure 1: Systems biology of the protease web.
Figure 2: Matrix metalloproteinase signal dynamic changes in the extracellular environment.

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Acknowledgements

This work was supported by grants from the National Cancer Institute of Canada with funds raised by the Canadian Cancer Association, the Canadian Breast Cancer Research Alliance special programme grant on metastasis, and with a Centre Grant from the Michael Smith Research Foundation. We gratefully acknowledgement the useful discussions of these concepts with Joerg Eder, Novartis Institutes of Biomedical Research, Basel, Switzerland.

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  1. the University of British Columbia Centre for Blood Research, CBCRA Program in Breast Cancer Metastasis Departments of Oral Biological & Medical Sciences and Biochemistry & Molecular Biology, University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada

    Christopher M. Overall

  2. the University of British Columbia Centre for Blood Research, CBCRA Program in Breast Cancer Metastasis, Departments of Oral Biological & Medical Sciences, and Biochemistry & Molecular Biology, University of British Columbia, Vancouver, V6T 1Z3, British Columbia, Canada

    Oded Kleifeld

  3. the University of British Columbia Centre for Blood Research, 4.401 Life Sciences Institute, 2350 Health Sciences Mall, Vancouver, V6T 1Z3, British Columbia, Canada

    Christopher M. Overall

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National Cancer Institute

breast cancer

FURTHER INFORMATION

Cancer degradome

Christopher Overall's laboratory, web page

Human, mouse and rat degradomes

MEROPS peptidase database

The CLIP-CHIP

The International Proteolysis Society

Peptidase nomenclature web site of the NC-IUBMB

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Overall, C., Kleifeld, O. Validating matrix metalloproteinases as drug targets and anti-targets for cancer therapy. Nat Rev Cancer 6, 227–239 (2006). https://doi.org/10.1038/nrc1821

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