Exploiting the Twist1 network in cancer cachexia

利用 Twist1 网络治疗癌症恶病质

• 批准号: 10203885
• 负责人: Azeddine Atfi
• 金额: $ 35.82万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 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/10203885
• 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

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.

项目总结 癌症恶病质是一种影响绝大多数晚期癌症患者的衰弱综合征。 占癌症相关死亡人数的近30%。缺乏用于识别患者的预后指标 敏感性和有效的治疗选择是癌症恶病质知识的主要空白。一把钥匙 癌症恶病质的特征是骨骼质量的进行性耗尽，这在一定程度上是由两个 分泌因子，激活素和肌肉抑制素。新出现的研究表明，药物抑制作用 激活素/肌肉抑制素信号足以抑制恶病质并延长几种小鼠模型的生存时间 癌症恶病质，增加了靶向这一途径可能代表着一种有希望的策略 遏制癌症患者的恶病质及其伴随的发病率和死亡率。 我们最近报道了Twist1在肌祖细胞中的过表达导致严重的 肌肉萎缩类似于癌症恶病质。使用几种胰腺癌的遗传小鼠模型，我们检测到 恶病质肌肉中Twist1表达的大量增加。我们还发现，升高的水平 在癌症患者中，肌肉扭曲与严重的恶病质有关。Twist1已停用，或者 从基因或药理上讲，对癌症引起的肌肉恶病质提供了实质性的保护， 这就转化为有意义的生存利益。从机械论的角度来看，我们提出的证据是 肿瘤来源的Act-A诱导Twist1的表达，进而驱动MuRF1和Atrogin1的表达， 导致肌肉蛋白质降解和伴随的恶病质。最后，我们发现Twist1也可以诱导 Myostatin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/肌肉抑制素信号转导中发挥作用 在癌症进展过程中协调前馈循环以执行肌肉恶病质。我们还假设 开发针对Twist1和Activin/Myostatin的联合治疗策略可能 通过降低每种药物所需的剂量来减轻潜在的药物毒性，并与开发 抵抗的力量。这些最重要的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，重点是它的调节能力 激活素引起的肌肉衰竭。 具体目标2：探索Twist1协调前馈环路以维持的机制 激活素/肌肉抑制素在癌症恶病质进展过程中导致的肌肉损失。 具体目标-3：测试针对Twist1和Twist1和Twist1的联合药物方案的疗效 激活素/肌肉抑制素信号通路与癌症恶病质 对这种新发现的恶病质驱动因素的全面描述可能会打开一个新的角度 恶病质领域，无论是在理解其机制范例方面，还是在药物发现方面。