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Targeting Adipocyte Lipases to Treat Pancreatic Cancer-Associated Cachexia

靶向脂肪细胞脂肪酶治疗胰腺癌相关恶病质

基本信息

批准号：
8708010
负责人：
Enrique Saez
金额：
$ 19.99万
依托单位：
SCRIPPS RESEARCH INSTITUTE, THE
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：
2013-07-29 至 2015-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8708010
关键词：
Ablation Accounting Address Adipocytes Adipose tissue Adverse effects Antineoplastic Agents Atrophic Biochemical Biological Assay Body Weight Body Weight decreased Cachexia Cancer Patient Cancer cell line Caspase Catecholamines Cell Death Cells Chemicals Diagnosis Disease Effectiveness Endoplasmic Reticulum Enzymes Exocrine pancreas Fatty acid glycerol esters Functional disorder Genetic Glycerol HIV Health Heart Human Hypertriglyceridemia Inflammatory Insulin Knockout Mice Libraries Lipase Lipids Lipolysis Malignant Neoplasms Malignant neoplasm of pancreas Manuscripts Medical Metabolic Methods Molecular Target Mus Natriuretic Peptides Nature Non-Insulin-Dependent Diabetes Mellitus Nonesterified Fatty Acids Obesity Pancreatic Adenocarcinoma Pancreatic Ductal Adenocarcinoma Patients Pharmaceutical Preparations Plasma Process Quality of life Risk Serine Hydrolase Skeletal Muscle Staging TNF gene Testing Therapeutic Time Tissues Toxic effect Treatment Failure Triglycerides Tumor-Derived Work adipocyte differentiation base blood lipid conventional therapy cytokine db/db mouse diabetic effective therapy feeding glucose tolerance improved in vivo inhibitor/antagonist insulin sensitivity interest lipid biosynthesis mortality multicatalytic endopeptidase complex muscle degeneration muscle form outcome forecast palliative pancreatic cancer cells public health relevance screening skeletal small molecule sterol esterase success therapeutic target tool tumor wasting

项目摘要

DESCRIPTION (provided by applicant): Cachexia is a progressive atrophy of adipose tissue and skeletal muscle that occurs in more than 85% of pancreatic ductal adenocarcinoma (PDAC) patients. It is a major contributor to the mortality of patients and an independent predictor of shorter survival. Cachexia dramatically reduces the quality of life of PDAC patients and increases the risk of treatment failure and toxicity. Treatments against cachexia are palliative in nature: there is no effective therapy for cancer-associated cachexia. Recently, increased interest has focused on tackling cachexia by attempting to revert the metabolic alterations that are associated with cachexia. A key feature in cancer cachexia is the loss of adipose tissue. Studies in humans have shown that increased adipocyte lipolysis, not reduced lipogenesis or increased fat cell death, is the primary cause of fat loss in cancer cachexia. Treating cancer patients with agents that address the adipocyte dysfunction that is the basis of the cachexia, in combination with standard antineoplastic agents, may dramatically enhance their quality of life and the chances of success of the anti-tumor treatment. All enzymes known to be involved in adipocyte lipolysis (ATGL, HSL, MGLL) are serine hydrolases. Genetic ablation of adipose triglyceride lipase (ATGL) and to a lesser extent hormone sensitive lipase (HSL) can protect from cancer-associated cachexia, demonstrating that correction of the adipocyte dysfunction is indeed a viable approach to reverse cancer-associated cachexia. However, systemic inhibition of these serine hydrolases is predicted to have deleterious effects that preclude this approach to treat cachexia. For example, ATGL null mice accumulate lipid in the heart and die prematurely. Integrating phenotypic screening with chemoproteomic methods, we recently identified another serine hydrolase, Ces3, which regulates adipocyte lipolysis. Pharmacologic inhibition of Ces3 ameliorates multiple features type 2 diabetes (another condition that involves increased rate of adipocyte lipolysis) without inducing side effects. We intend to evaluate the therapeutic potential of Ces3 inhibition in pancreatic cancer-associated cachexia, and to identify additional poorly annotated serine hydrolases that may serve as targets in cancer-associated cachexia.

描述（由申请人提供）：恶病质是一种脂肪组织和骨骼肌的进行性萎缩，发生在超过 85% 的胰腺导管腺癌 (PDAC) 患者中。它是患者死亡率的主要原因，也是较短生存期的独立预测因素。恶病质显着降低 PDAC 患者的生活质量，并增加治疗失败和毒性的风险。针对恶病质的治疗是姑息治疗性质：目前尚无有效治疗癌症相关恶病质的方法。最近，人们越来越关注通过尝试恢复与恶病质相关的代谢改变来解决恶病质。癌症恶病质的一个关键特征是脂肪组织的损失。人类研究表明，癌症恶病质中脂肪减少的主要原因是脂肪细胞脂肪分解增加，而不是脂肪生成减少或脂肪细胞死亡增加。使用解决恶病质基础的脂肪细胞功能障碍的药物与标准抗肿瘤药物相结合来治疗癌症患者，可以显着提高他们的生活质量和抗肿瘤治疗的成功机会。所有已知参与脂肪细胞脂肪分解的酶（ATGL、HSL、MGLL）都是丝氨酸水解酶。脂肪甘油三酯脂肪酶（ATGL）和激素敏感性脂肪酶（HSL）的基因消除可以预防癌症相关的恶病质，这表明纠正脂肪细胞功能障碍确实是逆转癌症相关的恶病质的可行方法。然而，预计这些丝氨酸水解酶的全身抑制会产生有害作用，从而阻碍了这种治疗恶病质的方法。例如，ATGL 缺失的小鼠在心脏中积聚脂质并过早死亡。将表型筛选与化学蛋白质组学方法相结合，我们最近鉴定了另一种丝氨酸水解酶 Ces3，它调节脂肪细胞脂肪分解。 Ces3 的药理学抑制可改善 2 型糖尿病（另一种涉及脂肪细胞脂解率增加的疾病）的多种特征，且不会引起副作用。我们打算评估治疗潜力 Ces3 抑制在胰腺癌相关恶病质中的作用，并鉴定其他注释不良的丝氨酸水解酶，这些酶可能作为癌症相关恶病质的靶标。