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PMID: 20818376 Published · ppublish English Journal Article

Allosteric inhibition of lysyl oxidase-like-2 impedes the development of a pathologic microenvironment.

Nature medicine ·Vol. 16 ·No. 9 ·2010-09-00 ·Pages 1009-17

Barry-Hamilton V, Spangler R, Marshall D, McCauley S, Rodriguez HM, Oyasu M, Mikels A, Vaysberg M, Ghermazien H, Wai C, Garcia CA, Velayo AC, Jorgensen B, Biermann D, Tsai D, Green J, Zaffryar-Eilot S, Holzer A, Ogg S, Thai D, Neufeld G, Van Vlasselaer P, Smith V

Abstract

We have identified a new role for the matrix enzyme lysyl oxidase-like-2 (LOXL2) in the creation and maintenance of the pathologic microenvironment of cancer and fibrotic disease. Our analysis of biopsies from human tumors and fibrotic lung and liver tissues revealed an increase in LOXL2 in disease-associated stroma and limited expression in healthy tissues. Targeting LOXL2 with an inhibitory monoclonal antibody (AB0023) was efficacious in both primary and metastatic xenograft models of cancer, as well as in liver and lung fibrosis models. Inhibition of LOXL2 resulted in a marked reduction in activated fibroblasts, desmoplasia and endothelial cells, decreased production of growth factors and cytokines and decreased transforming growth factor-beta (TGF-beta) pathway signaling. AB0023 outperformed the small-molecule lysyl oxidase inhibitor beta-aminoproprionitrile. The efficacy and safety of LOXL2-specific AB0023 represents a new therapeutic approach with broad applicability in oncologic and fibrotic diseases.

MeSH Terms
Amino Acid Oxidoreductases/antagonists & inhibitors,drug effects,genetics,metabolism Aminopropionitrile/pharmacology Animals Antibodies, Monoclonal/pharmacology Breast Neoplasms/pathology Cell Line, Tumor Female Humans Lactones/pharmacology Mice Mice, Nude Neoplasm Metastasis/pathology,prevention & control Polyenes/pharmacology RNA, Small Interfering/genetics Transcription, Genetic Transfection Transplantation, Heterologous
Chemicals
Antibodies, Monoclonal Lactones Polyenes RNA, Small Interfering Aminopropionitrile Amino Acid Oxidoreductases LOXL2 protein, human Loxl2 protein, mouse
Authors & Affiliations
23 authors, click to expand affiliations / ORCID
Barry-Hamilton Vivian
Arresto BioSciences, Palo Alto, California, USA.
Spangler Rhyannon
Marshall Derek
McCauley Scott
Rodriguez Hector M
Oyasu Miho
Mikels Amanda
Vaysberg Maria
Ghermazien Haben
Wai Carol
Garcia Carlos A
Velayo Arleene C
Jorgensen Brett
Biermann Donna
Tsai Daniel
Green Jennifer
Zaffryar-Eilot Shelly
Holzer Alison
Ogg Scott
Thai Dung
Neufeld Gera
Van Vlasselaer Peter
Smith Victoria
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Article Info
Journal
Nature medicine
Abbr.
Nat Med
ISSN
1546-170X
DOI
10.1038/nm.2208
Published
2010-09-00
Epub
2010-00-05
Pages
1009-17
Language
English
Region
United States
NLM ID
9502015
Subset
IM
Corrections
CommentIn
PMID: 21030997
External Links
PubMed source DOI: 10.1038/nm.2208 View journal details
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