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.

项目概要：肥胖和癌症之间的联系在流行病学上已得到充分证实，但人们对肥胖和癌症之间的联系知之甚少。机械层面。透明细胞肾细胞癌 (ccRCC) 是最常见的肾癌形式，与代谢综合征有明确的联系。 ccRCC 同时展示了在最近发现组织学和分子水平对于肿瘤的发展至关重要。然而，目前 ccRCC 的护理标准是针对酪氨酸激酶的靶向治疗，包括 VEGF 受体，在大多数情况下会适度改善总体生存率。从而识别出需要新的方法来治疗 ccRCC，而改变代谢可能提供临床上有用的立足点。我们研究了 ccRCC 的特征性脂质储存表型并确定了分子机制这部分是由肥胖造成的。本申请集中于由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。分泌的本质因素导致诊断和治疗潜力，在这里我们研究抑制该因素的影响脂肪因子 Chemerin，有多种方法，包括在临床前动物模型中使用单克隆抗体 ccRCC 和基因工程小鼠模型 (GEMM)。我们还将剖析其作用机制 Chemerin 对肿瘤和非肿瘤细胞的作用，并检查所收集的 Chemerin 亚型的意义临床标本。总之，该提案的目的是验证 ccRCC 中的一个新目标，该目标可以与现有疗法相结合，以改善患者的治疗效果。