Targeting Transglutaminase 2 in cancer cachexia

靶向转谷氨酰胺酶 2 治疗癌症恶病质

基本信息

批准号：
10442384
负责人：
Azeddine Atfi
金额：
$ 32.45万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10442384
关键词：
Achievement Advanced Malignant Neoplasm Affect Area Attenuated Cachexia Cancer Patient Cells Cessation of life Complex Complication Coupled Data Defect Development Diagnosis Disease Dose Drug Targeting Drug toxicity Ectopic Expression Enzymes Etiology FBXO32 gene Functional disorder Gene Expression Genetic Glutamine Impairment Incidence Individual Knowledge Lead Life Lysine Malignant Neoplasms Mediating Medical Medicine Metabolic Modeling Modification Muscle Muscle Proteins Muscle Weakness Muscle satellite cell Muscular Atrophy Organ Pathway interactions Patients Pharmacology Play Predisposition Process Prognostic Marker Quality of life Reporting Research Research Proposals Resistance development Respiratory Failure Role Syndrome Testing Therapeutic Treatment-Related Cancer Tumor-Derived Wasting Syndrome Weight activin A base cancer cachexia clinically relevant combat combinatorial comorbidity crosslink design drug candidate drug discovery effective therapy experimental study genetic approach improved in vivo inhibitor innovation mouse model novel pancreatic cancer patients pancreatic ductal adenocarcinoma model programs promoter protective effect protein degradation skeletal therapeutic evaluation transcription factor transglutaminase 2 tumor progression ubiquitin ligase

项目摘要

PROJECT SUMMARY Cachexia has a devastating impact on survival and quality of life of many cancer patients and remains an unmet medical need. Pancreatic cancer patients present with the highest incidence of cachexia (~90%), and approximately one-third of these patients lose more than 10% of their pre-illness weight, leading to general muscle weakness, impairment of normal activities, and eventually death through respiratory failure. A deeper understanding of the underlying mechanisms that lead to the complex metabolic defects of cachexia, coupled with effective treatment options, would improve management of muscle wasting in cancer patients. We have recently reported that ectopic expression of the transcription factor Twist1 in muscle progenitor cells is sufficient to cause severe muscle atrophy akin to muscle cachexia. Using several genetic mouse models of pancreatic ductal adenocarcinoma (PDAC), we detected high Twist1 expression in muscle undergoing cancer cachexia. Of particular importance, inactivating muscle Twist1, either genetically or pharmacological, was sufficient to reverse muscle cachexia and improve survival in several genetic mouse models of cancer cachexia, implicating Twist1 as a possible target for attenuating muscle cachexia in cancer patients. Quite serendipitously, we found that muscle Twist1 was highly crosslinked during cancer cachexia. We obtained strong evidence that this process was mediated by the crosslinking enzyme Transglutaminase 2 (TGM2). Treatment of cells with a specific TGM2 inhibitor completely suppressed Twist1-induced expression of MuRF1 and Atrogin1, two ubiquitin ligases that drive muscle protein degradation during muscle cachexia. Other preliminary data showed that expression of Twist1 in vivo promotes muscle TGM2 expression. More crucially, we detected a marked increase in both muscle Twist1 and TGM2 expression in cachectic cancer patients as compared to healthy individuals, attesting to the clinical relevance of our findings. Based on these intriguing findings, we hypothesize that TGM2 might function in partnership with Twist1 to orchestrate a feed-forward network that initiates and sustains muscle cachexia during cancer progression. We also hypothesize that developing combinatorial therapeutic strategies targeting both TGM2 and Twist1 could mitigate potential drug toxicity by lowering the dose needed for each medicine and combat the development of resistance. These overarching hypotheses will be tested in our research proposal. Specific Aim 1: Investigate the relationship between TGM2 and Twist1 during muscle cachexia Specific Aim 2: Explore the role of the TGM2-Twist1 axis in muscle cachexia using genetic approaches Specific Aim 3: Test the therapeutic value of targeting both TGM2 and Twist1 in muscle cachexia We believe that our innovative proposal to exploit this novel TGM2/Twist1 axis in muscle cachexia will culminate in a paradigm shift in our understanding and therapeutic treatment of this lethal wasting syndrome.

项目概要恶病质对许多癌症患者的生存和生活质量具有毁灭性影响，并且仍然是一个未得到解决的问题医疗需要。胰腺癌患者恶病质发生率最高（~90%），并且大约三分之一的患者体重比病前减轻了 10% 以上，导致全身肌肉无力，正常活动受损，最终因呼吸衰竭而死亡。更深层次的了解导致恶病质复杂代谢缺陷的潜在机制，结合通过有效的治疗方案，将改善癌症患者肌肉萎缩的管理。我们最近报道了转录因子 Twist1 在肌肉祖细胞中的异位表达细胞足以引起类似于肌肉恶病质的严重肌肉萎缩。使用多种基因小鼠模型在胰腺导管腺癌 (PDAC) 中，我们在患有癌症的肌肉中检测到 Twist1 高表达恶病质。特别重要的是，通过基因或药理学方法使肌肉 Twist1 失活足以逆转肌肉恶病质并提高几种癌症恶病质遗传小鼠模型的生存率，表明 Twist1 是减轻癌症患者肌肉恶病质的可能靶标。非常偶然的是，我们发现肌肉 Twist1 在癌症恶病质期间高度交联。我们获得强有力的证据表明该过程是由交联酶转谷氨酰胺酶 2 介导的（TGM2）。用特定的 TGM2 抑制剂处理细胞完全抑制 Twist1 诱导的表达 MuRF1 和 Atrogin1，两种泛素连接酶，在肌肉恶病质期间驱动肌肉蛋白降解。其他初步数据表明，体内Twist1的表达促进肌肉TGM2的表达。更关键的是，我们检测到恶病质癌症患者的肌肉 Twist1 和 TGM2 表达显着增加，与健康个体相比，证明了我们的研究结果的临床相关性。基于这些有趣的发现，我们假设 TGM2 可能与 Twist1 合作发挥作用协调一个前馈网络，在癌症进展过程中启动并维持肌肉恶病质。我们还假设开发针对 TGM2 和 Twist1 的组合治疗策略可以通过降低每种药物所需的剂量来减轻潜在的药物毒性，并阻止药物的发展反抗。这些总体假设将在我们的研究计划中得到检验。具体目标 1：研究肌肉恶病质期间 TGM2 和 Twist1 之间的关系具体目标 2：利用遗传方法探索 TGM2-Twist1 轴在肌肉恶病质中的作用具体目标 3：测试靶向 TGM2 和 Twist1 对肌肉恶病质的治疗价值我们相信，我们利用这种新型 TGM2/Twist1 轴治疗肌肉恶病质的创新提案将会达到顶峰我们对这种致命消耗综合症的理解和治疗发生了范式转变。