Journal
MOLECULAR CANCER THERAPEUTICS
Volume 15, Issue 5, Pages 890-898Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-15-0847
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Funding
- NIH [1R01CA135401-01A1, 1R03CA181837-01, 1R01DK082690-01A1]
- Medical Service of the US Department of Veterans' Affairs
- Dialysis Clinics, Inc. (DCI)
- NIEHS [R01 ES002710, P42 ES004699]
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Kidney cancer is the sixth most common cancer in the United States, and its incidence is increasing. The treatment of this malignancy took a major step forward with the recent introduction of targeted therapeutics, such as kinase inhibitors. Unfortunately, kinase inhibition is associated with the onset of resistance after 1 to 2 years of treatment. Regorafenib, like many multikinase inhibitors, was designed to block the activities of several key kinase pathways involved in oncogenesis (Ras/Raf/MEK/ERK) and tumor angiogenesis (VEGF-receptors), and we have recently shown that it also possesses soluble epoxide hydrolase (sEH) inhibitory activity, which may be contributing to its salutary effects in patients. Because sEH inhibition results in increases in the DHA-derived epoxydocosapentaenoic acids that we have previously described to possess anticancer proper-ties, we asked whether the addition of DHA to a therapeutic regimen in the presence of regorafenib would enhance its beneficial effects in vivo. We now show that the combination of regorafenib and DHA results in a synergistic effect upon tumor invasiveness as well as p-VEGFR attenuation. In addition, this combination showed a reduction in tumor weights, greater than each agent alone, in a mouse xenograft model of human renal cell carcinoma (RCC), yielding the expected oxylipin profiles; these data were supported in several RCC cell lines that showed similar results in vitro. Because DHA is the predominant component of fish oil, our data suggest that this nontoxic dietary supplement could be administered with regorafenib during therapy for advanced RCC and could be the basis of a clinical trial. (C) 2016 AACR.
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