ArticleClinical cancer research : an official journal of the American Association for Cancer Research2015
Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer.
Article in Clinical cancer research : an official journal of the American Association for Cancer Research, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 52 papers.
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52 citing papers in PubMed, 80 citations in OpenAlex.
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- Overexpression of SPHK1 associated with targeted therapy resistance in predicting poor prognosis in renal cell carcinoma.Translational cancer research · 2023Article
- Lipids as Targets for Renal Cell Carcinoma Therapy.International journal of molecular sciences · 2023Review
- Effects of adipocyte-conditioned cell culture media on S1P treatment of human triple-negative breast cancer cells.PloS one · 2023Article
- The m6A-regulation and single cell effect pattern in sunitinib resistance on clear cell renal cell carcinoma: Identification and validation of targets.Frontiers in pharmacology · 2023Article
- The cuproptosis-associated 13 gene signature as a robust predictor for outcome and response to immune- and targeted-therapies in clear cell renal cell carcinoma.Frontiers in immunology · 2022Article
- Development of a Novel Sphingolipid Signaling Pathway-Related Risk Assessment Model to Predict Prognosis in Kidney Renal Clear Cell Carcinoma.Frontiers in cell and developmental biology · 2022Article
- Article
- Interaction of microRNAs with sphingosine kinases, sphingosine-1 phosphate, and sphingosine-1 phosphate receptors in cancer.Discover oncology · 2021Review
- Targeting the Sphingosine Kinase/Sphingosine-1-Phosphate Signaling Axis in Drug Discovery for Cancer Therapy.Cancers · 2021Review
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16 authors at 2 institutions in 1 country.
Funding
Abstract
purposeVEGFR2 tyrosine kinase inhibition (TKI) is a valuable treatment approach for patients with metastatic renal cell carcinoma (RCC). However, resistance to treatment is inevitable. Identification of novel targets could lead to better treatment for patients with TKI-naïve or -resistant RCC. EXPERIMENTAL
designIn 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 sphingosine-1-phosphate (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.
resultsResistant 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 overproduction 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.
conclusionsOur 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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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.