Adipokine Signaling as a Therapeutically Targetable Driver of Tumor Metabolism

脂肪因子信号传导作为肿瘤代谢的治疗靶向驱动因素

• 批准号: 10580769
• 负责人: Scott Michael Welford
• 金额: $ 35.3万
• 依托单位: UNIVERSITY OF MIAMI SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-03-05 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10580769
• 关键词: Adipocytes; Allografting; Animal Model; Automobile Driving; Biological Markers; Carnitine Palmitoyltransferase I; Catabolism; Cell Death; Cell Line; Cells; Cessation of life; Characteristics; Clear cell renal cell carcinoma; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Cytometry; Cytoplasm; Data; Deposition; Development; Diagnostic; Dose; Endocrine Glands; Epidemiology; Fatty acid glycerol esters; Genes; Genetic; Genetic Transcription; Genetically Engineered Mouse; Glycogen; Glycolysis; High Fat Diet; Histologic; Human; Hypoxia Inducible Factor; Image; Immunocompetent; Incidence; Inflammatory; Intervention; Invaded; Iron; KDR gene; Knockout Mice; Lead; Lesion; Link; Lipids; Malignant Neoplasms; Mediating; Metabolic; Metabolic syndrome; Metabolism; Mitochondria; Modeling; Molecular; Monitor; Monoclonal Antibodies; Mus; Nature; Neoplasm Transplantation; Obesity; Oncogenic; Outcome; PF4 Gene; Pathogenesis; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Production; Protein Isoforms; Protein Tyrosine Kinase; Radiation therapy; Refractory; Regimen; Regulation; Renal Cell Carcinoma; Renal carcinoma; Resistance development; Risk Factors; Role; Sampling; Signal Transduction; Specimen; Stress; System; Testing; Therapeutic; Therapeutically Targetable; Tissues; Toxic effect; Tumor Promotion; Tumor Suppressor Proteins; Tumor-infiltrating immune cells; Tyrosine Kinase Inhibitor; adipokines; angiogenesis; autocrine; cancer risk; chemotherapy; deprivation; fatty acid transport; gene repression; improved; in silico; lipid biosynthesis; lipid metabolism; multiple omics; neoplastic cell; novel; novel strategies; novel therapeutics; overexpression; oxidation; paracrine; pre-clinical; prevent; prognostic; receptor; response; restoration; small hairpin RNA; standard of care; targeted agent; targeted treatment; transdifferentiation; tumor; tumor growth; tumor metabolism; tumor-immune system interactions; tumorigenesis

Project Summary: The link between obesity and cancer is well-established epidemiologically, but poorly understood at a mechanistic level. Clear cell renal cell carcinoma (ccRCC) is the most common form of renal cancer, and has clear ties with metabolic syndrome. ccRCC simultaneously demonstrates drastic metabolic rewiring at the histological and molecular levels that recently have been found to be essential for tumor development. Currently, however, the standard of care for ccRCC is targeted therapeutics against tyrosine kinases including the VEGF receptor, that in most cases lead to modest improvements in overall survival. Thus identification of new approaches to treat ccRCC is needed, and altered metabolism may offer a clinically useful foothold. We have investigated the characteristic lipid storage phenotype of ccRCC and identified a molecular mechanism that is driven in part by obesity. The present application focusses on a soluble adipokine produced by fat and tumors that suppresses lipid catabolism, and is essential for tumor growth. The very nature of a secreted factor leads to both diagnostic and therapeutic potential, and here we investigate the impact of inhibiting the adipokine, Chemerin, with multiple approaches including a monoclonal antibody in preclinical animal models of ccRCC, and a genetically engineered mouse model (GEMM). We will also dissect the mechanisms of action of Chemerin on tumor and non-tumor cells, and examine the significance of Chemerin isoforms in collected clinical specimens. Together, the aim of the proposal is to validate a novel target in ccRCC that could be combined with existing therapies to improve patient outcomes.

项目总结： 肥胖症和癌症之间的联系在流行病学上已经得到了很好的证实，但在 机械化水平。肾透明细胞癌(CcRCC)是最常见的肾癌， 与代谢综合征有明显联系。CcRCC同时展示了在 组织学和分子水平，最近被发现对肿瘤的发展是必不可少的。 然而，目前对ccRCC的标准治疗是针对酪氨酸激酶的靶向治疗，包括 血管内皮生长因子受体，这在大多数情况下会导致总体存活率的适度改善。从而识别出 需要治疗慢性肾细胞癌的新方法，改变代谢可能提供一个临床上有用的立足点。我们 研究了ccRCC特有的储脂表型，并确定了其分子机制。 这在一定程度上是由肥胖推动的。本应用集中于一种由脂肪和 抑制脂质分解代谢的肿瘤，对肿瘤生长至关重要。一个秘密组织的本质 因素导致诊断和治疗的潜力，在这里，我们调查了抑制 脂肪因子，Chmerin，包括在临床前动物模型中的单抗在内的多种方法 CcRCC和基因工程小鼠模型(GEMM)。我们还将剖析其作用机制。 Chmerin对肿瘤和非肿瘤细胞的作用，并检测收集到的Chmerin亚型的意义 临床标本。总之，该提案的目的是验证ccrccc的一个新目标，该目标可能是 与现有疗法相结合，以改善患者的预后。