Modeling muscle wasting in cancer cachexia

恶病质是一种使人衰弱的综合征，它会导致严重的、非自愿的体重下降，原因是体内的 骨骼肌块。这种综合征发生在大多数癌症中，并导致大约1 占所有癌症死亡人数的三分之一。目前，还没有有效的治疗方法来对抗这种恶性疾病， 最近三期临床试验的令人失望的结果表明，恶病质的治疗不太可能 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临床前研究中使用的模型。这个 这些模型中最常见的是利用异种移植瘤在加速的 有大量肿瘤负荷的时间尺度不能反映恶病质癌症所经历的情况 病人。已经开始了新的努力，以生产更好地概括这些癌症的模型 肌肉丧失的发生率很高，例如胰腺癌。其中一种名为KPC的模型是一种基因上的 一种患胰腺癌的转基因小鼠，最近被描述为恶病质 表型。我们的实验室对KPC小鼠进行了调查，希望发现新的 肌肉萎缩的机制。然而，我们积累的数据表明，KPC鼠标不是 恶病质的真正典范。我们的目标是忠实地概括胰腺恶病质的表型 癌症患者，我们开发了另一种遗传小鼠模型，它显著地显示了一种强大的 肌肉丧失与肿瘤进展的相关性。我们假设这种新的老鼠模型 胰腺癌患者癌症引起肌肉萎缩的常见机制将是有用的 用于转化性研究和靶向治疗。为了检验这一假设，我们将通过1)验证模型 确定可与人类疾病中的恶病质相媲美的标志物；以及2)进行临床前 试验以确定抑制肌肉生长抑素/激活素途径的效果。实现我们的目标，即产生 真正的癌症恶病质小鼠模型将加速我们对癌症潜在原因的理解 肌肉萎缩，这应该转化为改善目前的抗恶病质治疗流水线。

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.