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: 8776933
• 负责人: Vinata B Lokeshwar
• 金额: $ 34.65万
• 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 2015-09-14
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8776933
• 关键词: Adjuvant; Angiogenesis Inhibitors; 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; 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; animal imaging; animal tissue; base; capillary; cell motility; choleretic; chromatin immunoprecipitation; clinical application; cytotoxicity; design; dietary supplements; efficacy testing; improved; in vivo; mRNA Expression; metastasis prevention; neoplastic cell; novel; overexpression; prevent; promoter; response; transcription factor; treatment strategy; tumor; tumor growth

* DESCRIPTION (provided by applicant): 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.

* 描述(由申请人提供)： 摘要：尽管进行了肾切除和辅助治疗，超过1/3的肾细胞癌(RCC)患者已经或发展为转移性RCC(MRCC)。肾细胞癌患者5年的存活率为10%。该项目的主要目标是制定以膳食补充剂为基础的肾癌预防和治疗策略。奈克萨瓦？(SF)是FDA批准的口服血管生成抑制剂，可使总存活率提高12-18%，使疾病稳定约8周，失败率高。虽然SF失败的原因尚不清楚，但其被UDP-葡萄糖醛酸基转移酶-1A9(A9)的葡萄糖醛酸化是可能的，因为葡萄糖醛酸化作用使SF失活。在这项申请中提出的初步结果首次表明，与SF-响应者相比，SF治疗失败的患者的肿瘤中A9水平和SF-葡萄糖醛酸化作用显著更高。此外，在亚洲和欧洲广泛使用的一种无毒的膳食补充剂Hymecroone(HC)通过下调A9的表达来抑制SF的葡萄糖醛酸化。在肾细胞癌和血管内皮细胞中，HC和SF联合应用可抑制细胞的活力、运动能力、侵袭能力和毛细血管形成。通过抑制肾癌和间质细胞中的新分子靶点，包括A9，联合应用废除了驱动肾癌细胞存活、转移和血管生成的信号通路。在不到消耗浓度的十倍时，HC与SF联合使用时，在SF耐药的RCC模型中完全消除了肿瘤的生长，没有毒性。组织和血浆中SF和HC的水平远高于HC+SF活动所需的剂量。中心假说是，通过抑制新的靶点，HC+SF组合废除了肾癌和内皮细胞的功能，从而防止和消除了肾癌的生长、血管生成和转移。为了验证这一假设，将在肾细胞癌和基质细胞共培养中检查HC+SF活性的分子基础。接下来将评估HC+SF的生物利用度和毒性，同时分析HC和SF作为预测肾癌转移和SF疗效的分子靶点。最后，将在自发性转移-原位肾细胞癌模型中检验HC+SF联合用药预防肿瘤生长和转移的有效性。影响：这项研究应该导致一种有效的预防和控制肾细胞癌的策略，将无毒膳食补充剂HC与SF相结合。在临床前模型中评估活性、生物利用度和毒性并预测反应可能会促进这种饮食组合的临床应用。