Lysophosphatidic Acid Receptor 1 Antagonist SAR100842 for Patients With Diffuse Cutaneous Systemic Sclerosis

Allanore, Yannick; Distler, Oliver; Jagerschmidt, Alexandre; Illiano, Stéphane; Ledein, Laetitia; Boitier, Eric; Agueusop, Inoncent; Denton, Christopher P.; Khanna, Dinesh

doi:10.1002/art.40547

Cited by 86 publications

(44 citation statements)

References 24 publications

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“…Although there is no existing approach to targeting ATX-LPA axis for cancer treatment, there is now sufficient evidence to establish that LPA is a significant inducer that increases tumor growth, metastasis, and loss of efficacy of chemotherapy and RT. Blocking LPA formation and signaling as part of cancer treatment has become possible because at least three inhibitors against LPA signaling have proven to be safe in clinical trials [ 144 , 145 , 158 ]. GLPG1690, which is an ATX inhibitor, is currently in a Phase 3 trial for IPF [ 144 ].…”

Section: Future Perspectivementioning

confidence: 99%

Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer

Brindley

Tang

Meng

et al. 2020

IJMS

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Autotaxin (ATX) is a secreted enzyme that produces lysophosphatidate (LPA), which signals through six G-protein coupled receptors, promoting tumor growth, metastasis, and survival from chemotherapy and radiotherapy. Many cancer cells produce ATX, but breast cancer cells express little ATX. In breast tumors, ATX is produced by tumor-associated stroma. Breast tumors are also surrounded by adipose tissue, which is a major bodily source of ATX. In mice, a high-fat diet increases adipocyte ATX production. ATX production in obesity is also increased because of low-level inflammation in the expanded adipose tissue. This increased ATX secretion and consequent LPA signaling is associated with decreased adiponectin production, which results in adverse metabolic profiles and glucose homeostasis. Increased ATX production by inflamed adipose tissue may explain the obesity-breast cancer association. Breast tumors produce inflammatory mediators that stimulate ATX transcription in tumor-adjacent adipose tissue. This drives a feedforward inflammatory cycle since increased LPA signaling increases production of more inflammatory mediators and cyclooxygenase-2. Inhibiting ATX activity, which has implications in breast cancer adjuvant treatments, attenuates this cycle. Targeting ATX activity and LPA signaling may potentially increase chemotherapy and radiotherapy efficacy, and decrease radiation-induced fibrosis morbidity independently of breast cancer type because most ATX is not derived from breast cancer cells.

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Section: Future Perspectivementioning

confidence: 99%

Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer

Brindley

Tang

Meng

et al. 2020

IJMS

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“…In contrast to previous findings of direct TRP channel activation [545], LPA18:1 more substantially activates satellite glial cells and Schwann cells, suggesting an indirect neuromodulatory action [546]. LPA receptor antagonists are under development, and being tested for a number of pathologies, with analgesia not as the primary focus [539,547,548].…”

Section: Y D R O X Y E I C O S a T E T R A E N O I C A C I D S ( H E mentioning

confidence: 76%

Novel Analgesics with Peripheral Targets

Ciotu

Fischer

2020

Neurotherapeutics

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A limited number of peripheral targets generate pain. Inflammatory mediators can sensitize these. The review addresses targets acting exclusively or predominantly on sensory neurons, mediators involved in inflammation targeting sensory neurons, and mediators involved in a more general inflammatory process, of which an analgesic effect secondary to an anti-inflammatory effect can be expected. Different approaches to address these systems are discussed, including scavenging proinflammatory mediators, applying anti-inflammatory mediators, and inhibiting proinflammatory or facilitating anti-inflammatory receptors. New approaches are contrasted to established ones; the current stage of progress is mentioned, in particular considering whether there is data from a molecular and cellular level, from animals, or from human trials, including an early stage after a market release. An overview of publication activity is presented, considering a IuPhar/BPS-curated list of targets with restriction to pain-related publications, which was also used to identify topics.

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“…Overall, our unprecedented results obtained with SAR100842 in animal models of skin fibrosis using therapeutics protocols and our data in dermal fibroblasts from systemic sclerosis patients indicate that the inhibition of LPA 1 receptor signalling could be a promising therapeutic strategy in both patients with inflammatory as well as non‐inflammatory subtypes of systemic sclerosis. Indeed, a recently performed Phase 2 trial with SAR100842 demonstrated the safety of the approach in these patients (Allanore et al, 2018; Khanna et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

Translational engagement of lysophosphatidic acid receptor 1 in skin fibrosis: from dermal fibroblasts of patients with scleroderma to tight skin 1 mouse

Ledein

Léger

Dees

et al. 2020

British J Pharmacology

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Background and Purpose: Genetic deletion and pharmacological studies suggest a role for lysophosphatidic acid (LPA 1) receptor in fibrosis. We investigated the therapeutic potential in systemic sclerosis (SSc) of a new orally active selective LPA 1 receptor antagonist using dermal fibroblasts from patients and an animal model of skin fibrosis. Experimental Approach: Dermal fibroblast and skin biopsies from systemic sclerosis patients were used. Myofibroblast differentiation, gene expression and cytokine secretion were measured following LPA and/or SAR100842 treatment. Pharmacolgical effect of SAR100842 was assessed in the tight skin 1 (Tsk1) mouse model. Key Results: SAR100842 is equipotent against various LPA isoforms. Dermal fibroblasts and skin biopsies from patients with systemic sclerosis expressed high levels of LPA 1 receptor. The LPA functional response (Ca 2+) in systemic sclerosis dermal fibroblasts was fully antagonized with SAR100842. LPA induced myofibroblast differentiation in systemic sclerosis dermal and idiopathic pulmonary fibrosis lung fibroblasts and the secretion of inflammatory markers and activated Wnt markers. Results from systemic sclerosis dermal fibroblasts mirror those obtained in a mouse Tsk1 model of skin fibrosis. Using a therapeutic protocol, SAR100842 consistently reversed dermal thickening, inhibited myofibroblast differentiation and reduced skin collagen content.

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Lysophosphatidic Acid Receptor 1 Antagonist SAR100842 for Patients With Diffuse Cutaneous Systemic Sclerosis

Cited by 86 publications

References 24 publications

Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer

Role of Adipose Tissue-Derived Autotaxin, Lysophosphatidate Signaling, and Inflammation in the Progression and Treatment of Breast Cancer

Novel Analgesics with Peripheral Targets

Translational engagement of lysophosphatidic acid receptor 1 in skin fibrosis: from dermal fibroblasts of patients with scleroderma to tight skin 1 mouse

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