Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer

Chang, Joan; Lucas, Morghan C.; Leonte, Lidia ELena; Garcia-Montolio, Marc; Singh, Lukram Babloo; Findlay, Alison D.; Deodhar, Mandar; Foot, Jonathan S.; Jarolimek, Wolfgang; Timpson, Paul; Erler, Janine T.; Cox, Thomas R.

doi:10.18632/oncotarget.15257

Cited by 94 publications

(90 citation statements)

References 35 publications

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“…Recent studies simultaneously targeting LOX and LOXL2 with small molecule inhibitors (53) lend support to this hypothesis. Further studies, including double conditional Loxl2/Lox KO mice, are required to clarify the relationship between these LOX members in the metastatic process.…”

Section: Discussionmentioning

confidence: 93%

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

et al. 2017

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The lysyl oxidase-like protein LOXL2 has been suggested to contribute to tumor progression and metastasis, but in vivo evidence has been lacking. Here we provide functional evidence that LOXL2 is a key driver of breast cancer metastasis in two conditional transgenic mouse models of PyMT-induced breast cancer. LOXL2 ablation in mammary tumor cells dramatically decreased lung metastasis, whereas LOXL2 overexpression promoted metastatic tumor growth. LOXL2 depletion or overexpression in tumor cells does not affect extracellular matrix stiffness or organization in primary and metastatic tumors, implying a function for LOXL2 independent of its conventional role in extracellular matrix remodeling. In support of this likelihood, cellular and molecular analyses revealed an association of LOXL2 action with elevated levels of the EMT regulatory transcription factor Snail1 and expression of several cytokines that promote pre-metastatic niche formation. Taken together, our findings established a pathophysiological role and new function for LOXL2 in breast cancer metastasis.

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Section: Discussionmentioning

confidence: 93%

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

et al. 2017

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“…Pharmaxis has developed a selective inhibitor of LOXL2 that is in pre‐clinical testing (Table , Entry 7) . However, the structure of this specific drug has not been disclosed.…”

Section: Modulation Of Loxl2 Activitymentioning

confidence: 99%

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

Chopra

Sangarappillai

Romero‐Canelón

et al. 2020

Advanced Therapeutics

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Lysyl oxidase‐like 2 (LOXL2) is an emerging drug target against metastatic disease owing to its role in the upregulation of key processes including epithelial‐mesenchymal transition (EMT) and invasion. Recent activity in the field of small molecule LOXL2 inhibitor development by pharmaceutical and academic laboratories has renewed interest in targeting LOXL2. Herein, 1) the viability of LOXL2 as a drug target for the treatment of metastatic disease through an investigation of its biological actions is determined; 2) the pitfalls of an antibody approach are considered; and 3) the small molecule approaches emerging in the scientific and patent literature are reviewed. This review identifies that LOXL2 is localized and active intracellularly and extracellularly in invasive cancer cells. LOXL2 has been implicated in a number of established signaling pathways involved in tumor progression, further highlighting its appeal as a target in metastatic disease. Previously, limited chemical inhibitors have been developed; however, their selectivity profile for the LOX family has proven controversial. Antibodies, such as simtuzumab, have been developed selectively against LOXL2. Simtuzumab, in particular, progresses into phase II trials but it was ultimately terminated. The small molecule inhibitors of LOXL2 are summarized, some of which are now in the early stages of clinical trials.

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“…However, this process is dysregulated in a range of diseases. Alterations of the ECM can arise from aberrant expression or turnover of matrix components, such as collagen, fibronectin and hyaluronan, or altered post‐translational modifications, such as collagen crosslinking by lysyl oxidase (Cox et al, ; Chang et al, ), lysyl hydroxylase and transglutaminase activity (Wells, ), or proteolytic matrix degradation. These ECM changes occur in both normal and diseased tissue, and their effect on intracellular signalling pathways is critical in the regulation of function and phenotype of cells residing within these tissues.…”

Section: Dynamics Of Extracellular Matrix Homeostasismentioning

confidence: 99%

The extracellular matrix as a key regulator of intracellular signalling networks

Hastings

Skhinas

Fey

et al. 2018

British J Pharmacology

171

120

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The extracellular matrix (ECM) is a salient feature of all solid tissues within the body. This complex, acellular entity is composed of hundreds of individual molecules whose assembly, architecture and biomechanical properties are critical to controlling the behaviour and phenotype of the different cell types residing within tissues. Cells are the basic unit of life and the core building block of tissues and organs. At their simplest, they follow a set of rules, governed by their genetic code and effected through the complex protein signalling networks that these genes encode. These signalling networks assimilate and process the information received by the cell to control cellular decisions that govern cell fate. The ECM is the biggest provider of external stimuli to cells and as such is responsible for influencing intracellular signalling dynamics. In this review, we discuss the inclusion of ECM as a central regulatory signalling sub-network in computational models of cellular decision making, with a focus on its role in diseases such as cancer. LINKED ARTICLES: This article is part of a themed section on Translating the Matrix. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v176.1/issuetoc.

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Pre-clinical evaluation of small molecule LOXL2 inhibitors in breast cancer

Cited by 94 publications

References 35 publications

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

Lysyl Oxidase–like Protein LOXL2 Promotes Lung Metastasis of Breast Cancer

Lysyl Oxidase Like‐2 (LOXL2): An Emerging Oncology Target

The extracellular matrix as a key regulator of intracellular signalling networks

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