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具有破坏性影响， 医疗需求。胰腺癌患者恶病质的发生率最高（约90%）， 这些患者中约有三分之一的人体重减轻超过患病前体重的10%，导致一般性肥胖。 肌肉无力，正常活动受损，最终因呼吸衰竭而死亡。更深 了解导致恶病质复杂代谢缺陷的潜在机制， 与有效的治疗方案，将改善管理肌肉萎缩的癌症患者。 我们最近报道了转录因子Twist 1在肌肉祖细胞中的异位表达， 细胞足以引起严重的肌肉萎缩，类似于肌肉恶病质。使用几种遗传小鼠模型 胰腺导管腺癌（PDAC），我们检测到高Twist 1表达的肌肉发生癌症 恶病质特别重要的是，失活肌肉扭曲1，无论是遗传还是药理学， 足以逆转肌肉恶病质和提高癌症恶病质的几种遗传小鼠模型的存活率， 提示Twist 1可能是减轻癌症患者肌肉恶病质的靶点。 非常偶然的是，我们发现肌肉Twist 1在癌症恶病质期间高度交联。我们 我获得了强有力的证据表明，这一过程是由交联酶转氨酶2介导的 （TGM2）。用特异性TGM 2抑制剂处理细胞完全抑制Twist 1诱导的 MuRF 1和Atrogin 1，两种在肌肉恶病质期间驱动肌肉蛋白降解的泛素连接酶。其他 初步数据显示Twist 1在体内的表达促进肌肉TGM 2的表达。更关键的是， 我们检测到恶病质癌症患者肌肉Twist 1和TGM 2表达显著增加， 与健康个体相比，证明了我们的发现的临床相关性。 基于这些有趣的发现，我们推测TGM 2可能与Twist 1合作发挥作用。 协调一个前馈网络，在癌症进展过程中启动和维持肌肉恶病质。我们 我还假设，开发针对TGM 2和Twist 1的组合治疗策略， 通过降低每种药物所需的剂量来减轻潜在的药物毒性， 阻力这些总体假设将在我们的研究提案中进行测试。 具体目的1：研究肌肉恶病质期间TGM 2和Twist 1的关系 具体目标2：使用遗传方法探索TGM 2-Twist 1轴在肌肉恶病质中的作用 具体目标3：测试靶向TGM 2和Twist 1在肌肉恶病质中的治疗价值 我们相信，我们的创新建议，利用这一新的TGM 2/Twist 1轴在肌肉恶病质将达到高潮， 在我们对这种致命的消耗综合症的理解和治疗上的一个范式转变。