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

基本信息

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
项目类别：
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

项目摘要

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.

项目摘要：肥胖与癌症之间的联系在流行病学上是良好的，但在一个机械水平。透明细胞肾细胞癌（CCRCC）是肾癌最常见的形式，并且具有与代谢综合征的明确关系。 CCRCC同时证明了在最近发现的组织学和分子水平对于肿瘤发展至关重要。但是，目前，CCRCC的护理标准是针对酪氨酸激酶的针对性治疗方法在大多数情况下，VEGF受体会导致整体生存的适度改善。因此识别需要新的治疗CCRCC的方法，而改变的新陈代谢可能会提供临床上有用的立足点。我们已经研究了CCRCC的特征性脂质存储表型，并确定了分子机制这部分是由肥胖驱动的。目前的应用集中于脂肪和脂肪产生的可溶性脂肪因子抑制脂质分解代谢的肿瘤，对于肿瘤生长至关重要。分泌的本质因子会导致诊断和治疗潜力，在这里我们研究抑制脂肪因子，化学蛋白，采用多种方法，包括临床前动物模型中的单克隆抗体 CCRCC和基因工程的小鼠模型（GEMM）。我们还将剖析行动机制在肿瘤和非肿瘤细胞上进行chemerin，并检查了化学素同工型在收集的临床标本。该提案的目的在一起是验证CCRC中的新目标结合现有的疗法以改善患者预后。