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Clin Cancer Res. 2015 Apr 15;21(8):1925-1934. doi: 10.1158/1078-0432.CCR-14-2031. Epub 2015 Jan 14.

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

Author information

1
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.
2
Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, Boston, Massachusetts, 02215, United States of America.
3
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, Massachusetts, 02115, United States of America.
4
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.
5
Lpath Inc., 4025 Sorrento Valley Blvd. San Diego, CA, 92121, United States of America.
6
Department of Biology, San Diego State University, 5500 Campanile Dr. San Diego, CA. 92182-4614, United States of America.
7
Departments of Oncology and Medicine, Georgetown-Lombardi Comprehensive Cancer Center, 3970 Reservoir Road, NW, Washington, DC. United States of America.
#
Contributed equally

Abstract

PURPOSE:

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.

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 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.

PMID:
25589614
PMCID:
PMC4419371
DOI:
10.1158/1078-0432.CCR-14-2031
[Indexed for MEDLINE]
Free PMC Article

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