Abstract
Metastatic melanoma remains a devastating disease with a 5-year survival rate of less than five percent. Despite recent advances in targeted therapies for melanoma, only a small percentage of melanoma patients experience durable remissions. Therefore, it is critical to identify new therapies for the treatment of advanced melanoma. Here, we define connective tissue growth factor (CTGF) as a therapeutic target for metastatic melanoma. Clinically, CTGF expression correlates with tumor progression and is strongly induced by hypoxia through HIF-1 and HIF-2-dependent mechanisms. Genetic inhibition of CTGF in human melanoma cells is sufficient to significantly reduce orthotopic tumor growth, as well as metastatic tumor growth in the lung of severe combined immunodeficient (SCID) mice. Mechanistically, inhibition of CTGF decreased invasion and migration associated with reduced matrix metalloproteinase-9 expression. Most importantly, the anti-CTGF antibody, FG-3019, had a profound inhibitory effect on the progression of established metastatic melanoma. These results offer the first preclinical validation of anti-CTGF therapy for the treatment of advanced melanoma and underscore the importance of tumor hypoxia in melanoma progression.
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Acknowledgements
We thank members of the Giaccia Laboratory for their insightful discussions. We kindly thank Dr Boris C Bastian for discussions and review of our tissue array analysis methodology and Dr Adam J Krieg for his insights on the microarray analysis. We appreciate Kathy Brown's guiding hand with the low passage melanoma cell lines. This investigation was supported by NIH grants CA67166 and CA116685 (AJG), CA120526 (MBP), T32 CA121940 (ECF) and T32 CA09302 (TRW).
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Author notes
- C-F Cheng
Current address: Biomedical Technology and Device Research Labs., Industrial Technology Research Institute, Hsinchu, Taiwan.
Affiliations
Division of Radiation and Cancer Biology, Department of Radiation Oncology, Stanford University, Stanford, CA, USA
- E C Finger
- , C-F Cheng
- , T R Williams
- , E B Rankin
- , L Tachiki
- , A J Giaccia
- & M B Powell
Department of Biochemistry, Case Western Reserve University School of Medicine, Cleveland, OH, USA
- B Bedogni
FibroGen Inc., San Francisco, CA, USA
- S Spong
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Competing interests
Elizabeth C Finger, Chieh-Fang Cheng, Erinn B Rankin, Tiffany R Williams, Barbara Bedogni, Amato J Giaccia and Marianne Broome Powell declare no conflict of interest. Dr Susanne Spong is an employee of FibroGen Inc., and provided the FG-3019 antibody for investigation to the laboratory of Dr Amato Giaccia. FibroGen did not provide any funds for these experiments nor were they involved in the plans, design or analysis of the data.
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Correspondence to M B Powell.
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https://doi.org/10.1038/onc.2013.47
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