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  • Review Article
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Strategies for MMP inhibition in cancer: innovations for the post-trial era

Nature Reviews Cancer volume 2, pages 657–672 (2002)Cite this article

Key Points

  • The 24 human matrix metalloproteinases (MMPs) degrade all the main protein components of the extracellular matrix and basement membrane; are overexpressed in human tumours; and were originally associated with peritumour tissue degradation and metastasis formation. As MMPs are promising therapeutic targets, an intensive drug discovery programme led to many clinical trials of MMP inhibitors (MMPIs) for cancer therapy. However, until very recent reports of success in gastric carcinoma, these trials have largely been disappointing.

  • Many MMPs have been identified over the past two decades and these enzymes are now known to be mediators of a number of important normal cell processes. MMPs are involved in the early stages of cancer, explaining the failure of many of the MMPIs in late-stage cancer clinical trials.

  • A greater understanding of the regulatory mechanisms that control MMP transcription, activation and inhibition provides several new avenues for therapeutic intervention. Many new drugs are designed to target these key regulatory points.

  • MMP gene transcription can be inhibited by targeting extracellular factors or their cognate cell-surface receptors, signal-transduction pathways and nuclear factors that activate expression of these genes. MMP activation can also be inhibited by targeting proteases that cleave and activate MMPs.

  • New classes of inhibitors that mask MMP substrate cleavage sites or block the substrate-binding exosites, MMP-activatable cytotoxics and gene-targeting strategies offer alternative approaches for MMP inhibition in cancer.

  • Degradomic techniques can be developed to profile the protease expression pattern in tumours. Degradomic monitoring of the tumour should be complemented by use of surrogate markers for assessment of in vivo MMP activity and inhibition during treatment. However, the lack of practical surrogate markers that are available now is a problem that urgently needs addressing to improve the specificity and clinical efficacy of MMPI-based therapies.

Abstract

For more than two decades, the view that tumour-associated matrix metalloproteinases (MMPs) were required for peritumour tissue degradation and metastasis dominated the drive to develop MMP inhibitors as anticancer therapeutics. Until recently, clinical trials with MMP inhibitors have yielded disappointing results, highlighting the need for better insight into the mechanisms by which this growing family of multifunctional enzymes contribute to tumour growth. It is now recognized that MMP activity is tightly regulated at several levels, providing new avenues for blocking these enzymes. What are the different approaches that can be used to target MMPs, and which of these might lead to new therapeutic strategies for cancer?

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Figure 1: Human MMPs.
Figure 2: Levels of regulation of MMP expression and activity.
Figure 3: Regulatory elements in the promoter regions of human MMP genes.
Figure 4: Signalling pathways involved in MMP gene transcription, and potential strategies for therapeutic intervention.
Figure 5: Strategies for blocking proMMP activation.

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Acknowledgements

We thank all members of our labs for their helpful comments on the manuscript and apologize for omission of relevant works due to space constraints. C.M.O. is supported by a Canada Research Chair in Metalloproteinase Biology, and by grants from the National Cancer Institute of Canada, Canadian Institutes for Health Research, the Protein Engineering Network of Centers of Excellence and the Canadian Arthritis Network of Centers of Excellence. C.L-O. is supported by the Comisión Interministerial de Ciencia y Tecnología-Spain and by the European Union. The Instituto Universitario de Oncología is supported by Obra Social Cajastur-Asturias, Spain.

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Authors and Affiliations

  1. Departments of Oral Biological and Medical Sciences, and Biochemistry and Molecular Biology, C.I.H.R. Group in Matrix Dynamics, University of British Columbia, V6T 1Z3, Canada

    Christopher Mark Overall

  2. Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Instituto Universitario de Oncología, Universidad de Oviedo, Oviedo, 33006, Spain

    Carlos López-Otín

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  1. Christopher Mark Overall
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DATABASES

Cancer.gov

bladder cancer

breast cancer

gastric carcinoma

Kaposi's sarcoma

lymphoma

multiple myeloma

non-small-cell lung cancer

ovarian cancer

pancreatic carcinoma

renal-cell carcinoma

LocusLink

ADAMTS-1

ADAMTS-2

ADAMTS-3

ADAMTS-4

ADAMTS-5

ADAMTS-8

ADAMTS-13

ADAMTS-14

agrin

αvβ3 integrin

β1-integrin

bFGF

C/EBP

CBFA1

CD40L

chymase

CIZ

type I collagen

type IV collagen

CREB

EGF

EGR1

endostatin

ERK1

ERK2

ETS

FASL

FOS

furin

hemopexin

IFN-α

IFN-β

IFN-γ

IκB

IL-1

IL-4

IL-13

JUN

α2-macroglobulin

MAPK

MMP-1

MMP-2

MMP-3

MMP-7

MMP-9

MMP-11

MMP-13

MMP-14

MMP-23A

MMP-23B

MMP-28

MT1-MMP

MT2-MMP

NF-κB

p53

PCPE

plasmin

PTEN

RAS

RECK

SPC1

STAT1

TCF4

TEL

testican-3

TFPI2

TGF-β

thrombospondin-1

thrombospondin-2

TIMP1

TIMP-2

TIMP-3

TIMP-4

TNF-α

tryptase

VEGF

Medscape DrugInfo

gemcitabine

Periostat

temozolomide

OMIM

Ehlers–Danlos syndrome VIIC

rheumatoid arthritis

thrombotic thrombocytopenic purpura

Saccharomyces Genome DataBase

kex2

FURTHER INFORMATION

ADAMs and ADAMTSs

Aeterna Laboratories

Agouron Pharmaceuticals

British Biotech Pharmaceuticals

MEROPS database, version 5.7

MMP clinical trials

Glossary

BASEMENT MEMBRANE

A specialized form of extracellular matrix that is mainly composed of type IV collagen, nidogen, laminins and perlecan, and that separates epithelial cells from the underlying supporting stroma.

PROTEOLYTIC PROCESSING

Proteolysis that is distinct from degradation in that it represents highly specific and limited substrate cleavage, which results in a specific change of protein function.

S1′ SUBSITE

The active-site cleft of proteases can be topographically defined as a series of sites in which the substrate amino-acid residues bind. The subsites (S) that bind the substrate amino-acid residues amino-terminal of the scissile bond are consecutively numbered as S (unprimed subsites), whereas the subsites that are carboxy-terminal of the scissile bond are S′ (primed subsites). For MMPs, the S1′ site is the main specificity determinant.

GLUCOCORTICOIDS

Compounds that interact with specific steroid receptors and downregulate the expression of genes that mediate inflammatory processes.

DEGRADOMICS

The application of emerging genomic and proteomic approaches to the genetic, structural and functional characterization of proteases, their substrates and inhibitors on an organism-wide scale.

DEGRADOME

The complete set of proteases that is expressed at a specific time by a cell, tissue or organism. The degradome of a protease is its substrate repertoire.

PROTEASE CHIPS

Solid-phase devices for high-throughput analysis of proteases and their substrate repertoires at an organism, tissue or cellular level.

EXOSITE

A substrate-binding site that lies outside the active-site cleft of a protease and that is located on specialized substrate-binding modules/domains.

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Overall, C., López-Otín, C. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer 2, 657–672 (2002). https://doi.org/10.1038/nrc884

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