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）： 总结：超过三分之一的肾细胞癌（RCC）患者尽管接受了肾切除术和辅助治疗，仍患有或发展为转移性RCC（mRCC）。mRCC患者的5年生存率<10%。该项目的主要目标是制定针对mRCC的基于饮食依从性的预防和治疗策略。Nexavar？(SF)是一种FDA批准的口服血管生成抑制剂，可使总生存率提高12- 18%，使疾病稳定约8周，失败率高。虽然SF失效的原因尚不清楚，但其通过UDP-葡萄糖醛酸转移酶-1A9（A9）的葡萄糖醛酸化是合理的，因为葡萄糖醛酸化使SF失活。本申请中提供的初步结果首次表明，与SF应答者相比，SF治疗失败患者的肿瘤中A9水平和SF-葡萄糖醛酸化显著更高。此外，在亚洲和欧洲广泛使用的无毒膳食补充剂羟甲香豆素（HC）通过下调A9表达抑制SF葡萄糖醛酸化。在RCC和内皮细胞中，HC和SF的组合抑制活力、运动性、侵袭性和毛细血管形成。通过抑制RCC和基质细胞中的新分子靶点，包括A9，该组合废除了驱动RCC细胞存活，转移和血管生成的信号通路。在低于10倍的浓度下，HC与SF联合使用时完全消除了SF耐药RCC模型中的肿瘤生长，无毒性。SF和HC的组织和血浆水平远高于HC+SF活性所需的剂量。中心假设是通过抑制新靶点，HC+SF组合消除RCC和内皮细胞功能，从而预防和消除RCC生长、血管生成和转移。为了检验这一假设，将在RCC和基质细胞共培养物中检查HC+SF活性的分子基础。接下来将评价HC+SF的生物利用度和毒性，沿着分析HC和SF的分子靶点，作为生物标志物，以预测RCC转移和对SF的反应。最后，将在自发转移-原位RCC模型中检查HC+SF组合预防肿瘤生长和转移的功效。影响力：这项研究应该会产生一种有效的预防和控制mRCC的策略，将HC（一种无毒膳食补充剂）与SF结合起来。在临床前模型中评价活性、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。