Autotaxin inhibitors: a patent review

Barbayianni, Efrosini; Magrioti, Victoria; Moutevelis‐Minakakis, Panagiota; Kokotos, George

doi:10.1517/13543776.2013.796364

Cited by 63 publications

(58 citation statements)

References 70 publications

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“…Despite the availability of autotaxin inhibitors over the last decade, most do not have good bioavailability (Federico et al 2008, Albers & Ovaa 2012, Barbayianni et al 2013, Benesch et al 2014a. By contrast, a daily dosage of mice with ONO-8430506 substantially decreased plasma autotaxin activity and LPA concentrations, and it produced a 50-60% decrease in breast tumour (Benesch et al 2014b) and thyroid tumour growth.…”

Section: Discussionmentioning

confidence: 99%

Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer

Benesch¹,

Ko²,

Tang³

et al. 2015

Endocrine-Related Cancer

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Autotaxin is a secreted enzyme that converts extracellular lysophosphatidylcholine to lysophosphatidate (LPA). In cancers, LPA increases tumour growth, metastasis and chemoresistance by activating six G-protein coupled receptors. We examined O200 human thyroid biopsies. Autotaxin expression in metastatic deposits and primary carcinomas was four-to tenfold higher than in benign neoplasms or normal thyroid tissue. Autotaxin immunohistochemical staining was also increased in benign neoplasms with leukocytic infiltrations. Malignant tumours were distinguished from benign tumours by high tumour autotaxin, LPA levels and inflammatory mediators including IL1b, IL6, IL8, GMCSF, TNFa, CCL2, CXCL10 and platelet-derived growth factor (PDGF)-AA. We determined the mechanistic explanation for these results and revealed a vicious regulatory cycle in which LPA increased the secretion of 16 inflammatory modulators in papillary thyroid cancer cultures. Conversely, treating cancer cells with ten inflammatory cytokines and chemokines or PDGF-AA and PDGF-BB increased autotaxin secretion. We confirmed that this autotaxin/inflammatory cycle occurs in two SCID mouse models of papillary thyroid cancer by blocking LPA signalling using the autotaxin inhibitor ONO-8430506. This decreased the levels of 16 inflammatory mediators in the tumours and was accompanied by a 50-60% decrease in tumour volume. This resulted from a decreased mitotic index for the cancer cells and decreased levels of vascular endothelial growth factor and angiogenesis in the tumours. Our results demonstrate that the autotaxin/inflammatory cycle is a focal point for driving malignant thyroid tumour progression and possibly treatment resistance. Inhibiting autotaxin activity provides an effective and novel strategy for decreasing the inflammatory phenotype in thyroid carcinomas, which should complement other treatment modalities.

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Section: Discussionmentioning

confidence: 99%

Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer

Benesch¹,

Ko²,

Tang³

et al. 2015

Endocrine-Related Cancer

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“…diisocyanate asthma can be prevented. Treatment of symptoms should also be possible as there are effective low-molecular-weight ATX inhibitors (Albers et al, 2010;Barbayianni et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

Toluene diisocyanate: Induction of the autotaxin-lysophosphatidic acid axis and its association with airways symptoms

Broström

Axmon

et al. 2015

Toxicology and Applied Pharmacology

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“…Given the involvement of ATX-LPA receptor signaling in several pathologies, it is logical that much effort has been spent in developing specifi c ATX inhibitors both in academia and in industry ( 76 ). As an extracelullar PDE, ATX is an attractive and highly druggable target.…”

Section: Atx As a Drug Target: Small-molecule Inhibitorsmentioning

confidence: 99%