title: Anti-S1P Antibody as a Novel Therapeutic Strategy for VEGFR TKI-Resistant Renal Cancer.
abstract: OBJECTIVE
  VEGFR2 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.
  
  
  METHODS
  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 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.
  
  
  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 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.
  
  
  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.
authors.affiliation: Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, United States of America.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, United States of America.|Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, United States of America.
authors.forename: Xiaoen
authors.initials: X
authors.lastname: Wang
authors.affiliation: Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, United States of America.
authors.forename: Andrea J
authors.initials: AJ
authors.lastname: Bullock
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts, 02115, United States of America.
authors.forename: Marcella
authors.initials: M
authors.lastname: Callea
authors.affiliation: Division of Interdisciplinary Medicine and Biotechnology, and Genomics and Proteomics Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, United States of America.
authors.forename: Harleen
authors.initials: H
authors.lastname: Shah
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts, 02115, United States of America.
authors.forename: Jiaxi
authors.initials: J
authors.lastname: Song
authors.affiliation: Lpath Inc., 4025 Sorrento Valley Blvd. San Diego, CA, 92121, United States of America.
authors.forename: Kelli
authors.initials: K
authors.lastname: Moreno
authors.affiliation: Lpath Inc., 4025 Sorrento Valley Blvd. San Diego, CA, 92121, United States of America.
authors.forename: Barbara
authors.initials: B
authors.lastname: Visentin
authors.affiliation: Department of Biology, San Diego State University, 5500 Campanile Dr. San Diego, CA. 92182-4614, United States of America.
authors.forename: Douglas
authors.initials: D
authors.lastname: Deutschman
authors.affiliation: Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, United States of America.
authors.forename: David C
authors.initials: DC
authors.lastname: Alsop
authors.affiliation: Departments of Oncology and Medicine, Georgetown-Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, Washington, DC. United States of America.
authors.forename: Michael B
authors.initials: MB
authors.lastname: Atkins
authors.affiliation: Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, United States of America.
authors.forename: James W
authors.initials: JW
authors.lastname: Mier
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts, 02115, United States of America.
authors.forename: Sabina
authors.initials: S
authors.lastname: Signoretti
authors.affiliation: Division of Interdisciplinary Medicine and Biotechnology, and Genomics and Proteomics Center, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, United States of America.
authors.forename: Manoj
authors.initials: M
authors.lastname: Bhasin
authors.affiliation: Lpath Inc., 4025 Sorrento Valley Blvd. San Diego, CA, 92121, United States of America.
authors.forename: Roger A
authors.initials: RA
authors.lastname: Sabbadini
authors.affiliation: Division of Hematology-Oncology and Cancer Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, United States of America.
authors.forename: Rupal S
authors.initials: RS
authors.lastname: Bhatt
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D004195:Disease Models, Animal; D019008:Drug Resistance, Neoplasm; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D008246:Lysophospholipids / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000235:genetics / Q000378:metabolism; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D040262:Receptors, Vascular Endothelial Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000037:antagonists & inhibitors / Q000378:metabolism; D059467:Transcriptome; D047368:Tumor Burden / Q000187:drug effects; D015854:Up-Regulation; D023041:Xenograft Model Antitumor Assays; D000099157:Sphingosine Kinase
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D040262:Receptors, Vascular Endothelial Growth Factor; D013110:Sphingosine; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate