Targeting Transglutaminase 2 in cancer cachexia

靶向转谷氨酰胺酶 2 治疗癌症恶病质

• 批准号: 10032715
• 负责人: Azeddine Atfi
• 金额: $ 32.21万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 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/10032715
• 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; Muscular Atrophy; Organ; Pancreatic Ductal Adenocarcinoma; 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/antagonist; innovation; mouse model; novel; pancreatic cancer patients; programs; promoter; protective effect; protein degradation; skeletal; stem cells; therapeutic evaluation; transcription factor; transglutaminase 2; tumor progression; ubiquitin ligase

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.

项目摘要 恶病质对许多癌症患者的生存和生活质量有毁灭性的影响，并且仍然是一种未满足的 医疗需求。胰腺癌患者的患者发病率最高（〜90％），并且 这些患者中约有三分之一损失超过10％的胸部重量，导致一般 肌肉无力，正常活动的损害以及最终通过呼吸衰竭而死亡。更深 理解导致复杂代谢缺陷的基本机制，耦合 有了有效的治疗选择，可以改善癌症患者肌肉浪费的治疗。 我们最近报告说，肌肉祖细胞中转录因子扭曲1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。使用几种遗传小鼠模型 胰腺导管腺癌（PDAC）的肌肉腺癌（PDAC），我们在癌症中检测到高扭曲1的表达 卡希克西亚。尤其重要的是，在遗传学或药理上失活的肌肉扭曲是 足以逆转肌肉恶病质并改善癌症恶病质遗传小鼠模型的生存， 将Twist1视为癌症患者减弱肌肉恶病质的可能目标。 相当偶然地，我们发现肌肉扭曲1在癌症恶病质期间高度交联。我们 获得了有力的证据，表明该过程是由交联酶转谷氨酰胺酶2介导的 （TGM2）。用特定TGM2抑制剂对细胞的处理完全抑制了扭曲1诱导的表达 MURF1和Atrogin1，两个泛素连接酶，它们在肌肉缓存期间驱动肌肉蛋白质降解。其他 初步数据表明，体内扭曲1的表达促进肌肉TGM2表达。更重要的是， 我们检测 与健康的个体相比，证明我们发现的临床相关性。 基于这些有趣的发现，我们假设TGM2可能与Twist1合作起作用 策划一个前进网络，该网络在癌症进展过程中启动和维持肌肉恶病质。我们 还假设制定针对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并打击的发展，以减轻潜在的药物毒性 反抗。这些总体假设将在我们的研究建议中进行检验。 特定目标1：研究肌肉恶病质期间TGM2和Twist1之间的关系 特定目标2：探索使用遗传方法在肌肉恶病质中探索TGM2-TWIST1轴的作用 特定目标3：测试靶标在肌肉恶病质中靶向TGM2和Twist1的治疗价值 我们认为，我们的创新提议利用这部小说的TGM2/Twist1轴肌肉恶病质将达到顶峰 在我们对这种致命浪费综合征的理解和治疗治疗的范式转变中。