A phase I study of sonepcizumab (S), a humanized monoclonal antibody to sphingosine-1-phosphate (S1P), in patients with advanced solid tumors.

Gordon, Michael S.; Just, R.; Rosen, Lee S.; Dörr, Anne

doi:10.1200/jco.2010.28.15_suppl.2560

Cited by 13 publications

(8 citation statements)

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“…A Phase I safety study was recently completed for sonepcizumab. The ASONEP trial was a multi-center, open-label, single-arm, dose escalation study of sonepcizumab administered as a single agent weekly to subjects with refractory advanced solid tumors at doses between 1 and 24 mg/kg (50). Sonepcizumab was well tolerated with no dose-limiting toxicities observed.…”

Section: Discussionmentioning

confidence: 99%

Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer

Zhang

Wang

Bullock

et al. 2015

Clinical Cancer Research

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Purpose VEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic RCC. However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for both patients with TKI naïve or resistant RCC. Experimental design In this study, we performed transcriptome analysis of VEGFR TKI resistant tumors in a murine model and discovered that the SPHK/S1P pathway is upregulated at the time of resistance. We tested S1P pathway inhibition using an anti-S1P mAb (sphingomab), in two mouse xenograft models of RCC, and assessed tumor SPHK expression and S1P plasma levels in patients with metastatic RCC. Results Resistant tumors expressed several hypoxia regulated genes. The SPHK1 pathway was among the most highly upregulated pathways that accompanied resistance to VEGFR TKI therapy. SPHK1 was expressed in human RCC, and the product of SPHK1 activity, S1P, was elevated in patients with metastatic RCC suggesting that human RCC behavior could, in part, be due to over-production of S1P. Sphingomab neutralization of extracellular S1P slowed tumor growth in both mouse models. Mice bearing tumors that had developed resistance to sunitinib treatment also exhibited tumor growth suppression with sphingomab. Sphingomab treatment led to a reduction in tumor blood flow as measured by MRI. Conclusions Our findings suggest that S1P inhibition may be a novel therapeutic strategy in patients with treatment naïve RCC and also in the setting of resistance to VEGFR TKI therapy.

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Section: Discussionmentioning

confidence: 99%

Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer

Zhang

Wang

Bullock

et al. 2015

Clinical Cancer Research

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“…This patient has also shown significant symptomatic improvement (near elimination of the diarrhoea and flushing that makes carcinoid so debilitating). These data were presented at a recent ASCO meeting (Gordon et al ., 2010).…”

Section: S1p and Cancermentioning

confidence: 99%

Sphingosine‐1‐phosphate antibodies as potential agents in the treatment of cancer and age‐related macular degeneration

Sabbadini

2011

British J Pharmacology

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Sphingosine-1-phosphate (S1P) is a pleiotropic bioactive lipid thought to be dysregulated in a variety of disease conditions. In this review, we discuss the roles of S1P in cancer and in wet age-related macular degeneration. We also explore potential treatment strategies for these disorders, including the utility of anti-S1P antibodies acting as molecular sponges to neutralize dysregulated S1P in relevant tissues. AbbreviationsAMD, age-related macular degeneration; CNV, choroidal neovascularization; GLP, good laboratory practices; NHP, non-human primate; PED, pigmented epithelial detachment; RPE, retinal pigmented epithelium; S1P, sphingosine-1-phosphate; SphK, sphingosine kinase Sphingosine-1-phosphate is an attractive target for drug discoveryBioactive lipids are important signalling mediators that are becoming attractive targets for drug discovery because of their roles in cancer, inflammation and other pathological conditions. Examples of such bioactive lipids include: (i) eicosanoids (such as the thromboxanes and leukotrienes); (ii) phospholipids and their lysophospholipid derivatives such as platelet activating factor (PAF) and lysophosphatidic acid; and (iii) sphingolipids such as sphingosine-1-phosphate (S1P). In recent years, receptors and other targets have been discovered for many of these bioactive lipids, suggesting extracellular signalling roles for these lipid mediators and growth factors (Im, 2009). One difficulty in targeting proteins that are responsible for their dysregulation in disease is that there are commonly several biosynthetic pathways for a particular bioactive lipid. Equally challenging is that there are commonly several receptors, ion channels or other proteins responsible for the action of a particular bioactive lipid and, in some cases, not all of the receptors that have been elucidated as novel receptors continue to appear in the literature (Im, 2009).Of the 1000 or so bioactive lipids, sphingolipids are recognized as important intercellular and intracellular signalling molecules participating in physiological and pathological processes associated with cellular survival, proliferation, differentiation and adhesion function (Moolenaar, 1999;Goetzl et al., 2002;Birgbauer and Chun, 2006;Gardell et al., 2006). The key elements of the sphingomyelin-associated signalling pathway include the bioactive lipid mediators, ceramide (CER), sphingosine (SPH) and S1P.The most celebrated sphingolipid mediator is S1P whose well-documented pleiotropic biological activities are mediated via a family of G protein-coupled cell surface receptors (GPCRs) belonging to the family of endothelial differentiation genes (EDG). These high-affinity receptors are S1P 1-5/ EDG-1,3,5,6 and 8 and are coupled to heterotrimeric G-proteins (Gi/o, Gq-, Gi-, G12-13) and small GTPases of the Rho family (Anliker and Chun, 2004). Most of the BJP British Journal of Pharmacology DOI:10.1111DOI:10. /j.1476DOI:10. -5381.2010 British Journal of Pharmacology (2011) growth-promoting actions of S1P described in multiple organ sy...

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“…Additionally, sonepcizumab treatment was welltolerated in cancer patients, and it was demonstrated to be important in trafficking of lymphocytes. S1P activity was found to increase lymphocyte number, while sonepcizumab treatment was shown to decrease it [152,155].…”

Section: Sphingosine-1-phosphate Receptor Inhibitorsmentioning

confidence: 95%

Novel Agents Targeting Bioactive Sphingolipids for the Treatment of Cancer

Adan-Gokbulut¹,

Yandım²,

Iskender³

et al. 2012

CMC

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Sphingolipids are a class of lipids that have important functions in a variety of cellular processes such as, differentiation, proliferation, senescence, apoptosis and chemotherapeutic resistance. The most widely studied bioactive shingolipids include ceramides, dihydroceramide (dhCer), ceramide-1-phosphate (C1P), glucosyl-ceramide (GluCer), sphingosine and sphingosine-1-phosphate (S1P). Although the length of fatty acid chain affects the physiological role, ceramides and sphingosine are known to induce apoptosis whereas C1P, S1P and GluCer induce proliferation of cells, which causes the development of chemoresistance. Previous studies have implicated the significance of bioactive shingolipids in oncogenesis, cancer progression and drug-and radiation-resistance. Therefore, targeting the elements of sphingolipid metabolism appears important for the development of novel therapeutics or to increase the effectiveness of the current treatment strategies. Some approaches involve the development of synthetic ceramide analogs, small molecule inhibitors of enzymes such as sphingosine kinase, acid ceramidase or ceramide synthase that catalyze ceramide catabolism or its conversion to various molecular species and S1P receptor antagonists. These approaches mainly aim to up-regulate the levels of apoptotic shingolipids while the proliferative ones are down-regulated, or to directly deliver cytotoxic sphingolipids like short-chain ceramide analogs to tumor cells. It is suggested that a combination therapy with conventional cytotoxic approaches while preventing the conversion of ceramide to S1P and consequently increasing the ceramide levels would be more beneficial. This review compiles the current knowledge about sphingolipids, and mainly focuses on novel agents modulating sphingolipid pathways that represent recent therapeutic strategies for the treatment of cancer.

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A phase I study of sonepcizumab (S), a humanized monoclonal antibody to sphingosine-1-phosphate (S1P), in patients with advanced solid tumors.

Cited by 13 publications

References 0 publications

Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer

Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer

Sphingosine‐1‐phosphate antibodies as potential agents in the treatment of cancer and age‐related macular degeneration

Novel Agents Targeting Bioactive Sphingolipids for the Treatment of Cancer

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