The addition of fish oil to sorafenib may prevent kidney cancer metastasis

描述（由申请人提供）：肾细胞癌（RCC）是美国第六大常见癌症，每年折磨11，000名患者，并且是发病率正在增加的少数癌症之一。由于缺乏有效的治疗方法， 晚期诊断，转移性RCC患者的5年生存率仍然很低。对于三分之一处于转移阶段的患者，有几种FDA批准的药物可用，其中包括多激酶抑制剂和mTOR抑制剂。由于耐药性，即使使用这些新药，无进展生存期也只有一到两年，因此必须确定和验证转移性RCC患者的新治疗方法。索拉非尼是第一个FDA批准的晚期RCC的靶向治疗，主要通过其对VEGF的作用起作用，从而引起血管生成抑制。鉴于绝大多数RCC与VHL突变相关，因此具有高度血管生成性，任何增强现有药物抗血管生成作用的方法都将是RCC治疗的重大进展。我们之前已经证明了索拉非尼对酶可溶性环氧化物水解酶（sEH）的显著抑制作用，并且我们的初步数据显示sEH抑制剂与二十二碳六烯酸（DHA;鱼油的主要组分）的组合在各种癌症中具有协同抗血管生成作用。由于这些原因，我们假设在鱼油补充剂存在下索拉非尼对sEH的抑制稳定了环氧二十二碳五烯酸（EDP; DHA的代谢物），从而通过调节肿瘤血管生成来预防RCC转移。此外，我们有证据表明，鱼油补充剂降低了索拉非尼最普遍和致残的不良反应，全身性高血压。该项目的工作将首次证明，在FDA批准的药物索拉非尼中简单添加鱼油在预防和治疗晚期肾癌方面具有巨大潜力。

DESCRIPTION (provided by applicant): Renal cell carcinoma (RCC) is the sixth most common cancer in the U.S. afflicting 11,000 patients per year, and is one of the few cancers whose incidence is increasing. In light of the paucity of effective treatments and the frequency of late stage diagnosis, the 5-year survival of patients with metastatic RCC remains dismal. For the one-third of patients who present at the metastatic stage, there are several FDA-approved drugs available, among them the multi-kinase inhibitors and the mTOR inhibitors. Since progression-free survival even with these new drugs is only one to two years due to drug resistance, it is imperative that novel therapeutic approaches for patients with metastatic RCC be identified and validated. Sorafenib was the first FDA- approved targeted therapy for advanced RCC and works principally through its effect on VEGF and thus causes angiogenesis inhibition. Given that the vast majority of RCCs are associated with VHL mutations and are thus highly angiogenic, any means to augment the anti-angiogenic effects of existing drugs would be a major advance in the therapy of RCC. We have previously demonstrated a pronounced inhibitory effect of sorafenib's on the enzyme, soluble epoxide hydrolase (sEH), and our preliminary data show that the combination of sEH inhibitors with docosahexaenoic acid (DHA; a major component of fish oil) has synergistic anti-angiogenic effects in various cancers. For these reasons we hypothesize that sEH inhibition by sorafenib in the presence of fish-oil supplementation stabilizes epoxy docosapentaenoic acid (EDP; a metabolite of DHA) and thereby prevents RCC metastasis through modulation of tumor angiogenesis. In addition, we have evidence that fish-oil supplementation decreases the most prevalent and disabling adverse effect of sorafenib, systemic hypertension. Work in this project will demonstrate for the first time that the simple addition of fish oil to the FDA-approved drug sorafenib has great potential in the prevention and treatment of advanced kidney cancer.