Modeling muscle wasting in cancer cachexia

恶病质是一种使人衰弱的综合征，其导致严重的、非自愿的体重减轻，这是由于 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 三分之一的癌症死亡。目前，没有有效的治疗方法来对抗这种恶性疾病， 最近的III期临床试验结果令人失望，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目前的 癌症恶病质领域的大多数实验室在其临床前研究中使用的模型。的 这些模型中最常见的是利用小鼠，其中异种移植肿瘤在加速的生长过程中诱导肌肉损失。 具有大肿瘤负荷的时间尺度，不能反映恶病质癌症所经历的状况 患者新的努力已经启动，以产生更好地概括这些癌症的模型， 高发病率的肌肉损失，如胰腺癌。其中一种称为KPC的模型是基因 一种基因改造的小鼠，患有胰腺癌，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 肌肉萎缩的机制。然而，我们积累的数据表明，KPC小鼠不是一种 真正的恶病质模型我们的目标是忠实地概括胰腺癌中所见的恶病质表型， 癌症患者，我们开发了一种替代的遗传小鼠模型，显着，显示出强烈的 肌肉损失和肿瘤进展之间的相关性。我们假设这种新的小鼠模型 胰腺癌患者癌症引起的肌肉萎缩的共同机制， 用于转化研究和靶向治疗。为了验证这一假设，我们将验证模型1） 鉴定与人类疾病中的恶病质相当的标志物;和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，产生 真正的癌症恶病质小鼠模型将加速我们对癌症的根本原因的理解。 肌肉萎缩，这应该转化为改善目前的管道抗恶病质疗法。

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.