Exploiting the Twist1 network in cancer cachexia

利用 Twist1 网络治疗癌症恶病质

基本信息

批准号：
10402355
负责人：
Azeddine Atfi
金额：
$ 34.8万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-06-01 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10402355
关键词：
Activins Advanced Malignant Neoplasm Affect Antibodies Binding Body Weight decreased Cachexia Cancer Patient Cells Cessation of life Complication Development Diagnosis Dose Drug Targeting Drug toxicity FBXO32 gene GDF8 gene Genetic Genetically Engineered Mouse Incidence Knowledge Life Malignant Neoplasms Mediating Mediator of activation protein Medicine Mesenchymal Stem Cells Modeling Morbidity - disease rate Muscle Muscle Proteins Muscle satellite cell Muscular Atrophy Neoplasm Metastasis Pathway interactions Patients Pharmaceutical Preparations Pharmacology Play Predisposition Prognostic Marker Quality of life Regimen Reporting Resistance development Role Signal Pathway Signal Transduction Syndrome Testing Therapeutic Transforming Growth Factor beta Translating Tumor-Derived Wasting Syndrome activin A base cancer cachexia cancer survival chemotherapy clinically relevant combat combinatorial design drug discovery effective therapy efficacy testing experience in vivo innovation member mortality mouse model overexpression pancreatic cancer model pancreatic cancer patients pancreatic ductal adenocarcinoma model protein degradation receptor sarcoma skeletal skeletal muscle wasting stem cell fate transcription factor tumor tumor growth tumor progression ubiquitin ligase

项目摘要

PROJECT SUMMARY Cancer cachexia is a debilitating syndrome that affects the vast majority of patients with advanced cancer and accounts for nearly 30% of cancer-related deaths. The lack of prognostic markers to identify patient susceptibility and effective treatment options represent major gaps in cancer cachexia knowledge. A key feature of cancer cachexia is the progressive depletion of skeletal mass, which is mediated in part by two secreted factors, Activin and Myostatin. Emerging studies have revealed that pharmacological inhibition of Activin/Myostatin signaling is sufficient to suppress cachexia and extend survival in several mouse models of cancer cachexia, raising the possibility that targeting this pathway might represent a promising strategy to curb cachexia and attendant morbidity and mortality in cancer patients. We have recently reported that overexpression of Twist1 in muscle progenitor cells causes severe muscle loss akin to cancer cachexia. Using several genetic mouse models of pancreatic cancer, we detected a massive increase in Twist1 expression in muscle undergoing cachexia. We also found that elevated levels of muscle Twist1 are associated with severe cachexia in cancer patients. Inactivation of Twist1, either genetically or pharmacologically, afforded substantial protection against cancer-mediated muscle cachexia, which translated into meaningful survival benefits. From a mechanistic perspective, we present evidence that tumor-derived Act-A induces expression of Twist1, which in turn drives expression of MuRF1 and Atrogin1, leading to muscle protein degradation and attendant cachexia. Finally, we found that Twist1 also induces Myostatin expression, further supporting its role in cancer-driven muscle cachexia. Based on our findings, we hypothesize that Twist1 might function in Activin/Myostatin signaling to coordinate a feed-forward loop to execute muscle cachexia during cancer progression. We also hypothesize that developing combinatorial therapeutic strategies targeting both Twist1 and Activin/Myostatin 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 the following three Specific Aims: Specific Aim 1: Investigate the role of Twist1 in cancer cachexia, focusing on its ability to mediate Activin-induced muscle depletion. Specific Aim 2: Explore the mechanisms by which Twist1 coordinates a feed-forward loop to sustain Activin/Myostatin-driven muscle loss during cancer cachexia progression. Specific Aim-3: Test the efficacy of combinatorial drugs regimens targeting both Twist1 and Activin/Myostatin signaling pathway in cancer cachexia. Comprehensive characterization of this newly discovered cachexia driver will likely open up new angles to the cachexia field, both in terms of understanding its mechanistic paradigms and in terms of drug discovery.

项目概要癌症恶病质是一种使人衰弱的综合征，影响绝大多数晚期癌症患者占癌症相关死亡的近 30%。缺乏识别患者的预后标志物易感性和有效的治疗方案代表了癌症恶病质知识的主要差距。一把钥匙癌症恶病质的特征是骨骼质量的进行性消耗，这部分是由两种介导的分泌因子，激活素和肌肉生长抑制素。新兴研究表明，药理学抑制激活素/肌肉生长抑制素信号传导足以抑制恶病质并延长几种小鼠模型的生存期癌症恶病质，提高了针对该途径可能代表一种有前途的策略的可能性抑制癌症患者的恶病质以及随之而来的发病率和死亡率。我们最近报道，肌肉祖细胞中 Twist1 的过度表达会导致严重的肌肉损失类似于癌症恶病质。使用几种胰腺癌基因小鼠模型，我们检测到恶病质肌肉中 Twist1 表达大量增加。我们还发现水平升高肌肉 Twist1 的减少与癌症患者的严重恶病质有关。 Twist1 失活，或者遗传或药理学上，提供了针对癌症介导的肌肉恶病质的实质性保护，这转化为有意义的生存效益。从机制的角度来看，我们提供的证据表明肿瘤源性 Act-A 诱导 Twist1 表达，进而驱动 MuRF1 和 Atrogin1 表达，导致肌肉蛋白质降解和随之而来的恶病质。最后，我们发现 Twist1 还诱导肌肉生长抑制素的表达，进一步支持其在癌症驱动的肌肉恶病质中的作用。根据我们的发现，我们假设 Twist1 可能在激活素/肌肉生长抑制素信号传导中发挥作用协调前馈循环以在癌症进展期间执行肌肉恶病质。我们还假设开发针对 Twist1 和 Activin/Myostatin 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发展的阻力。这些总体假设将在以下三个具体目标中得到检验：具体目标 1：研究 Twist1 在癌症恶病质中的作用，重点关注其介导能力激活素诱导的肌肉耗竭。具体目标 2：探索 Twist1 协调前馈循环以维持的机制癌症恶病质进展期间激活素/肌肉生长抑制素驱动的肌肉损失。具体目标 3：测试针对 Twist1 和 Twist1 的组合药物方案的功效癌症恶病质中的激活素/肌肉生长抑制素信号通路。对这个新发现的恶病质驱动程序的全面表征可能会为研究开辟新的角度。恶病质领域，无论是在理解其机制范式还是在药物发现方面。