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

索拉非尼中添加鱼油可预防肾癌转移

基本信息

批准号：
8788395
负责人：
ROBERT H. WEISS
金额：
$ 7.8万
依托单位：
UNIVERSITY OF CALIFORNIA AT DAVIS
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-01-01 至 2015-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8788395
关键词：
Adverse effects Adverse event Angiogenesis Inhibition Arachidonic Acids BAY 54-9085 Benign Biological Factors Clinical Combined Modality Therapy Core Facility Data Diagnosis Disease Disease Resistance Docosahexaenoic Acids Drug resistance Enzymes Epoxide hydrolase FDA approved Fish Oils Fishes Frequencies Goals Growth Health Hypertension Image Analysis Imaging Techniques In Vitro Incidence Ingestion Laboratories Lead Light Luciferases Malignant Epithelial Cell Malignant Neoplasms Metabolic Metastatic Renal Cell Cancer Mus Neoplasm Metastasis Omega-3 Fatty Acids Patients Pharmaceutical Preparations Prevention Process Progression-Free Survivals Renal Cell Carcinoma Renal carcinoma Staging Supplementation Testing Therapeutic Time Tumor Angiogenesis VHL mutation Vascular Endothelial Growth Factors Work Workplace Xenograft procedure angiogenesis base bioimaging cell growth clinical efficacy dietary supplements docosapentaenoic acid effective therapy experience hypertension prevention improved in vivo in vivo Model inhibitor/antagonist kinase inhibitor mTOR Inhibitor metastasis prevention novel novel therapeutic intervention pleiotropism prevent research study success targeted treatment tumor growth

项目摘要

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.

描述（由申请人提供）：肾细胞癌（RCC）是美国第六个最常见的癌症，每年遭受11,000名患者，并且是少数发病率增加的癌症之一。鉴于有效治疗的匮乏和晚期诊断，转移性RCC患者的5年生存仍然令人沮丧。对于在转移阶段出现的三分之一的患者，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。由于无进展的生存率即使使用这些新药仅由于耐药性而仅是一到两年，因此必须确定和验证转移性RCC患者的新型治疗方法。索拉非尼是第一个经过FDA批准的针对晚期RCC的靶向疗法，主要通过其对VEGF的影响而起作用，从而导致血管生成抑制。鉴于绝大多数RCC都与VHL突变有关，因此具有高度的血管生成，因此任何增加现有药物的抗血管生成作用的方法将是RCC治疗的重大进步。我们以前已经证明了索拉非尼对酶，可溶性环氧水解酶（SEH）的明显抑制作用，我们的初步数据表明，SEH抑制剂与二战二甲己己烯酸（DHA； DHA； DHA；鱼油的主要成分；鱼油的主要成分）在各种Cancercers in Cancerscers synergistic抗体抗体作用。由于这些原因，我们假设在存在鱼油的情况下索拉非尼的SEH抑制稳定了环氧二十二碳烯酸（EDP； DHA代谢物），从而通过调节肿瘤血管生成来防止RCC转移。此外，我们有证据表明，补充鱼油会降低索拉非尼，全身性高血压的最普遍，最禁用的不良影响。该项目中的工作将首次证明，在FDA批准的索拉非尼中简单地将鱼油添加到预防和治疗晚期肾癌中具有巨大潜力。