Modeling muscle wasting in cancer cachexia

模拟癌症恶病质中的肌肉消耗

• 批准号: 9227697
• 负责人: Denis C Guttridge
• 金额: $ 20.33万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-20 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9227697
• 关键词: Activins; Adipose tissue; Advanced Malignant Neoplasm; Alleles; Animal Cancer Model; Animal Model; Anticachexia Agent; Automobile Driving; Biological Markers; Body Weight decreased; Cachexia; Cancer Patient; Cessation of life; Clinic; Clinical Trials; Colon; Communities; Data; Disease; Exhibits; GDF8 gene; Gene Expression; Genetic; Genetically Engineered Mouse; Goals; Incidence; Investigation; Kinetics; Laboratories; Lead; Lewis Lung Carcinoma; Link; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Modeling; Molecular; Morbidity - disease rate; Mus; Muscle; Muscle Weakness; Muscular Atrophy; Myomatous neoplasm; Pancreas; Pathway interactions; Patients; Phase III Clinical Trials; Phenotype; Publications; Publishing; Quality of life; Research; Research Personnel; Signal Pathway; Skeletal Muscle; Symptoms; Syndrome; TP53 gene; Testing; Time; Translating; Tumor Burden; Xenograft Model; base; cancer cachexia; cancer care; colon cancer patients; combat; effective therapy; end stage disease; experience; human disease; improved; mortality; mouse model; muscle form; mutant; neoplastic cell; pancreatic neoplasm; pre-clinical trial; preclinical study; prevent; skeletal muscle wasting; targeted treatment; translational study; tumor; tumor progression; tumor xenograft; wasting

Cachexia is a debilitating syndrome that results in severe, involuntary weight loss due to the depletion of skeletal muscle mass. This syndrome occurs in a majority of cancers and contributes to approximately one third of all cancer deaths. Currently, no effective therapy exists to combat this malignant disorder, and disappointing results from recent Phase III clinical trials indicate that a cachexia treatment is not likely to appear soon. A potential contributing factor to the lack of progress in the clinic may be linked to the current models that a majority of laboratories in the cancer cachexia field are using in their pre-clinical studies. The most common of these models utilize mice where xenograft tumors induce muscle loss on an accelerated time scale with a large tumor load that is not reflective of conditions experienced by cachectic cancer patients. New efforts have been launched to produce models that better recapitulate those cancers with a high incidence of muscle loss, such as pancreatic cancer. One such model called KPC is a genetically engineered mouse that develops pancreatic cancer and was recently described to exhibit a cachectic phenotype. Our laboratory pursued investigations with the KPC mouse in hopes of discovering new mechanisms of muscle wasting. However, data we have accumulated suggest that the KPC mouse is not a true model of cachexia. With our goal to faithfully recapitulate the cachexia phenotype seen in pancreatic cancer patients, we developed an alternative genetic mouse model, which significantly, shows a strong correlation between muscle loss and tumor progression. We hypothesize that this new mouse model shares common mechanisms of cancer-induced muscle wasting with pancreatic cancer patients and will be useful for translational studies and targeted therapeutics. To test this hypothesis we will validate the model by 1) identifying markers that are comparable to cachexia in the human disease; and 2) performing a pre-clinical trial to determine the efficacy of inhibiting the myostatin/activin pathway. Achieving our goal to generate a bona fide mouse model of cancer cachexia will accelerate our understanding of the underlying causes of muscle wasting, which should translate to improving the current pipeline of anti-cachexia therapies.

恶病质是一种使人衰弱的综合征，由于缺乏 骨骼肌质量。这种综合征发生在大多数癌症中，并导致大约一种 占所有癌症死亡人数的三分之一。目前，尚无有效的疗法来对抗这种恶性疾病，并且 最近的 III 期临床试验令人失望的结果表明恶病质治疗不太可能 很快就会出现。临床缺乏进展的一个潜在因素可能与当前的情况有关 癌症恶病质领域的大多数实验室在临床前研究中使用的模型。这 这些模型中最常见的是利用小鼠，其中异种移植肿瘤加速肌肉损失 具有大肿瘤负荷的时间尺度不能反映恶病质癌症经历的情况 患者。人们已经发起了新的努力，以建立能够更好地重现这些癌症的模型 肌肉损失的发生率很高，例如胰腺癌。一种称为 KPC 的模型是一种基因模型 基因工程小鼠患上胰腺癌，最近被描述为表现出恶病质 表型。我们的实验室对 KPC 小鼠进行了研究，希望能发现新的发现 肌肉萎缩的机制。然而，我们积累的数据表明 KPC 鼠标不是 恶病质的真实模型。我们的目标是忠实地重现胰腺中所见的恶病质表型 癌症患者中，我们开发了一种替代基因小鼠模型，该模型显着地显示出强大的 肌肉损失与肿瘤进展之间的相关性。我们假设这种新的小鼠模型共享 胰腺癌患者癌症引起的肌肉萎缩的常见机制，将很有用 用于转化研究和靶向治疗。为了检验这个假设，我们将通过 1) 来验证模型 识别与人类疾病中恶病质相当的标记； 2) 进行临床前 试验以确定抑制肌生长抑制素/激活素途径的功效。实现我们的目标 真正的癌症恶病质小鼠模型将加速我们对癌症恶病质根本原因的理解 肌肉萎缩，这应该转化为改善当前的抗恶病质疗法。