Dietary Combination For Prevention of Metastatic Renal Cell Carcinoma

预防转移性肾细胞癌的饮食组合

• 批准号: 8633231
• 负责人: Vinata B Lokeshwar
• 金额: $ 32.9万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-12-01 至 2018-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8633231
• 关键词: Adjuvant; Angiogenesis Inhibitors; Animals; Anticoagulants; Asia; BAY 54-9085; Binding; Biochemical; Biological Assay; Biological Availability; Biological Markers; Blood capillaries; Cell Survival; Cell physiology; Chemistry; Clinical; Coculture Techniques; Consumption; Country; Cystic kidney; Diet; Disease; Dose; Down-Regulation; Drug Kinetics; EMSA; Endothelial Cells; Europe; Evaluation; FDA approved; Failure; Fibroblasts; Future; Glucuronic Acids; Glucuronides; Glucuronosyltransferase; Goals; Growth; Health; Histology; Hyaluronic Acid; Image; Immunocompetent; In Situ; In Vitro; Investigation; Lead; Life; Liver; Luciferases; Malignant Epithelial Cell; Measures; Mediating; Metastatic Renal Cell Cancer; Modeling; Molecular; Molecular Target; Mus; Mutagenesis; Neoplasm Metastasis; Nephrectomy; Nexavar; Oral; Patients; Pharmacodynamics; Phenotype; Plasma; Pre-Clinical Model; Prevention; Prevention strategy; Property; Renal Cell Carcinoma; Resistance; Serum; Signal Pathway; Signal Transduction; Spasmolytics; Specimen; Staging; Stromal Cells; Testing; Time; Tissues; Toxic effect; Transgenic Model; Translations; Urine; Urology; Xenobiotics; angiogenesis; base; capillary; cell motility; choleretic; clinical application; cytotoxicity; design; dietary supplements; efficacy testing; improved; in vivo; mRNA Expression; metastasis prevention; neoplastic cell; novel; overexpression; prevent; promoter; public health relevance; response; transcription factor; treatment strategy; tumor; tumor growth

Summary: More than 1/3rd of renal cell carcinoma (RCC) patients either have or develop metastatic-RCC (mRCC) despite nephrectomy and adjuvant treatments. Survival of mRCC patients at 5-years is < 10%. The major goal of this project is to develop a dietary supplement-based prevention and treatment strategy against mRCC. Nexavar¿ (SF) is an FDA approved oral angiogenesis inhibitor which improves overall survival by 12- 18%, causes disease stabilization for about 8-weeks and has a high failure rate. Although the cause of SF failure is unknown, its glucuronidation by UDP-Glucuronyltransferase-1A9 (A9) is a plausible one, because glucuronidation inactivates SF. Preliminary results presented in this application show for the first time that when compared to the SF-responders, A9 levels and SF-glucuronidation are significantly higher in tumors from those patients who fail SF treatment. Furthermore, a non-toxic dietary supplement Hymecromone (HC), consumed extensively in Asia and Europe, inhibits SF glucuronidation by downregulating A9 expression. In RCC and endothelial cells, the combination of HC and SF inhibited viability, motility, invasion and capillary formation. By inhibiting novel molecular targets in RCC and stromal cells, including A9, the combination abrogated signaling pathways that drive RCC cell survival, metastasis and angiogenesis. At concentrations less than ten-fold of those used for consumption, HC when combined with SF completely eliminated tumor growth in a SF-resistant RCC model, without toxicity. Tissue and plasma levels of SF and HC were well above the doses needed for the activity of HC+SF. The central hypothesis is that by inhibiting novel targets, HC+SF combination abrogates RCC and endothelial cell functions leading to the prevention and elimination of RCC growth, angiogenesis and metastasis. To test this hypothesis, the molecular basis of HC+SF activity will be examined in RCC and stromal cell co-cultures. Next the bioavailability and toxicity of HC+SF will be evaluated, along with the analysis of the molecular targets of HC and SF, as biomarkers, to predict RCC metastasis and response to SF. Finally, the efficacy of the HC+SF combination, to prevent tumor growth and metastasis, will be examined in spontaneously metastatic-orthotopic RCC models. Impact: This study should lead to an effective strategy for the prevention and control of mRCC that combines HC, a non-toxic dietary supplement, with SF. Evaluation of activity, bioavailability and toxicity in pre-clinical models and prediction of response may advance this dietary combination for clinical application.

摘要：超过1/3的肾细胞癌（RCC）患者患有转移性RCC或发展 （MRCC）任务肾切除术和调整治疗方法。 MRCC患者在5年中的存活率<10％。这 该项目的主要目的是制定基于饮食补充剂的预防和治疗策略 MRCC。 Nexavar¿（SF）是FDA批准的口服血管生成抑制剂，将总生存率提高12- 18％，导致约8周的疾病稳定，并且失败率很高。虽然是SF的原因 失败是未知的，UDP-葡萄糖朗甘氨酸转移酶-1A9（A9）的谷氨酸化是合理的，因为 谷化使SF失活。本申请中提出的初步结果首次显示 与SF-RESPONDER相比，A9水平和SF-葡萄糖醛酸化的水平明显更高 那些失败的SF治疗的患者。此外，一种无毒的饮食补充性肌电剂（HC）， 在亚洲和欧洲大量食用，通过下调A9表达来抑制SF谷脲氮酸化。在 RCC和内皮细胞，HC和SF的组合抑制了活力，运动，入侵和毛细管 形成。通过抑制RCC和基质细胞中的新型分子靶标，包括A9，该组合 促使RCC细胞存活，转移和血管生成的急救信号通路。浓度 与SF结合使用时，HC不到十倍，HC完全消除了肿瘤 耐SF的RCC模型的增长，无毒性。 SF和HC的组织和血浆水平远高于 HC+SF活动所需的剂量。中心假设是通过抑制新型靶标HC+SF 组合消除了RCC和内皮细胞功能，导致预防和消除RCC 生长，血管生成和转移。为了检验该假设，HC+SF活性的分子基础将是 在RCC和基质细胞共培养中进行了检查。接下来，将评估HC+SF的生物利用度和毒性， 以及对HC和SF的分子靶标的分析，作为生物标志物，以预测RCC转移和 对SF的响应。最后，HC+SF组合的效率，以防止肿瘤生长和转移，将 在赞助的转移性反应性RCC模型中进行检查。 影响：这项研究应导致有效的预防和控制MRCC的策略 HC，一种无毒的饮食补充剂，带有SF。临床前的活动，生物利用度和毒性的评估 模型和反应的预测可能会推进这种饮食中的临床应用。