Exploiting the Twist1 network in cancer cachexia

利用 Twist1 网络治疗癌症恶病质

• 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
• 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

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.

项目摘要 癌症恶病质是一种衰弱的综合征，影响了绝大多数晚期癌症患者 占与癌症相关的死亡的近30％。缺乏预后标记来识别患者 敏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。钥匙 癌症恶病质的特征是骨骼质量的进行性耗竭，部分由两个 分泌的因素，激活素和肌生抑素。新兴研究表明，药理学抑制 激活素/肌汀信号足以抑制恶病病和延长几种小鼠模型的生存 癌症恶病质，提高了针对此途径可能代表有希望的策略的可能性 癌症患者的遏制恶病质和随之而来的发病率和死亡率。 我们最近报告说，肌肉祖细胞中扭曲1的过表达会导致严重 类似于癌症恶病质的肌肉损失。使用几种胰腺癌的遗传小鼠模型，我们检测到 经历恶病质的肌肉中扭曲1表达的大量增加。我们还发现升高的水平 肌肉扭曲1与癌症患者的严重恶病质有关。扭曲的灭活，要么 从遗传学或药理上，对癌症介导的肌肉恶病质提供了实质性的保护， 转化为有意义的生存优势。从机械的角度来看，我们提供证据表明 肿瘤衍生的ACT-A诱导Twist1的表达，这反过来驱动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也引起了 肌抑素的表达，进一步支持其在癌症驱动的肌肉缓存中的作用。 根据我们的发现，我们假设Twist1可能在激活素/肌抑制素信号中起作用 在癌症进展过程中协调一个前进环以执行肌肉恶病质。我们也假设 靶向扭曲1和激活素/肌抑素的组合治疗策略可以 通过降低每种药物所需的剂量并与发育作用来减轻潜在的药物毒性 阻力。这些总体假设将在以下三个具体目标中进行检验： 特定目标1：研究Twist1在癌症恶病质中的作用，重点是其介导的能力 激活素引起的肌肉耗竭。 特定目的2：探索Twist1协调前进环以维持的机制 癌症恶病质进展过程中激活素/肌动蛋白驱动的肌肉损失。 特定的AIM-3：测试针对Twist1和 癌症恶病质中的激活素/肌抑素信号通路。 这个新发现的恶病质驱动器的全面表征可能会与 在理解其机械范式和药物发现方面，恶病质领域。