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.

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