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

描述(申请人提供)：肾细胞癌(RCC)是美国第六大最常见的癌症，每年困扰11,000名患者，是少数几种发病率不断上升的癌症之一。鉴于缺乏有效的治疗方法和频发的 晚期诊断，转移性肾细胞癌患者的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批准的药物可供选择，其中包括多激酶抑制剂和mTOR抑制剂。由于耐药，即使使用这些新药，无进展生存期也只有一到两年，因此发现和验证转移性肾癌患者的新治疗方法是当务之急。索拉非尼是FDA批准的第一个治疗晚期肾癌的靶向药物，主要通过影响血管内皮生长因子而导致血管生成抑制。鉴于绝大多数肾细胞癌与VHL突变相关，因此具有高度的血管生成作用，因此，任何增强现有药物抗血管生成作用的手段都将是肾癌治疗的重大进展。我们之前已经证明索拉非尼对可溶性环氧化物水解酶(SEH)有显著的抑制作用，我们的初步数据表明sEH抑制剂与二十二碳六烯酸(DHA；鱼油的主要成分)在各种癌症中具有协同抗血管生成作用。由于这些原因，我们假设索拉非尼在补充鱼油的情况下抑制sEH可以稳定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防止肾癌转移。此外，我们有证据表明，补充鱼油可以降低索拉非尼最普遍和最无效的副作用，即全身性高血压。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地添加鱼油在预防和治疗晚期肾癌方面具有巨大的潜力。

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.