Dietary Combination For Prevention of Metastatic Renal Cell Carcinoma

预防转移性肾细胞癌的饮食组合

基本信息

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
项目类别：
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

项目摘要

* 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：尽管进行了肾切除术和辅助治疗，仍有超过 1/3 的肾细胞癌 (RCC) 患者患有或发展为转移性肾细胞癌 (mRCC)。 mRCC 患者的 5 年生存率 < 10%。该项目的主要目标是开发一种基于膳食补充剂的 mRCC 预防和治疗策略。多吉美？ (SF) 是 FDA 批准的口服血管生成抑制剂，可将总体生存率提高 12-18%，使疾病稳定约 8 周，但失败率很高。尽管 SF 失败的原因尚不清楚，但 UDP-葡萄糖醛酸转移酶-1A9 (A9) 对其进行葡萄糖醛酸化是一种合理的原因，因为葡萄糖醛酸化会使 SF 失活。本申请中提出的初步结果首次表明，与 SF 应答者相比，SF 治疗失败的患者肿瘤中的 A9 水平和 SF-葡萄糖醛酸化显着较高。此外，亚洲和欧洲广泛食用的无毒膳食补充剂 Hymecromone (HC) 通过下调 A9 表达来抑制 SF 葡萄糖醛酸化。在肾细胞癌和内皮细胞中，HC 和 SF 的组合抑制活力、运动、侵袭和毛细血管形成。通过抑制 RCC 和基质细胞中的新分子靶点（包括 A9），该组合消除了驱动 RCC 细胞存活、转移和血管生成的信号通路。在低于食用浓度十倍的情况下，HC 与 SF 结合可完全消除 SF 耐药性 RCC 模型中的肿瘤生长，且无毒性。 SF和HC的组织和血浆水平远高于HC+SF活性所需的剂量。核心假设是，通过抑制新靶标，HC+SF 组合消除了 RCC 和内皮细胞功能，从而预防和消除了 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。接下来将评估 HC+SF 的生物利用度和毒性，以及作为生物标志物的 HC 和 SF 的分子靶点分析，以预测 RCC 转移和对 SF 的反应。最后，将在自发转移性原位肾细胞癌模型中检查 HC+SF 组合预防肿瘤生长和转移的功效。影响：这项研究应该产生一种将 HC（一种无毒膳食补充剂）与 SF 相结合的预防和控制 mRCC 的有效策略。在临床前模型中评估活性、生物利用度和毒性以及预测反应可能会促进这种饮食组合的临床应用。