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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.

项目总结