Development of a clinically relevant mouse model of lung cancer cachexia to study pathoetiology and therapeutic strategies

项目总结 癌症恶病质(CC)的特征是继发于脂肪和骨骼的意外体重减轻 肌肉组织萎缩。它是肿瘤和宿主之间复杂的相互作用的结果，肿瘤在宿主中释放 这些因素会改变外周器官和组织的新陈代谢，从而导致消耗。CC影响大多数患者 对于肺癌，胰腺癌和胃肠癌，除了其他晚期癌症患者外， 与治疗相关的毒性增加，对化疗和免疫治疗的反应差，以及 据估计，在所有与癌症相关的死亡中，约20%是由癌症引起的。肺癌是第二常见的癌症。 在全球范围内，是与癌症相关的死亡的主要原因。大多数肺癌患者都表现出 CC在诊断时，高达75%的患者在治疗过程中经历组织浪费。致癌KRAS突变 增加CC的风险，并在许多易发生CC的侵袭性癌症中发现，包括胰腺癌， 胃肠道癌和肺癌。事实上，绝大多数肺腺癌显示出升高的证据 RAS通路激活(84%)。研究已经描述了具有突变的Kras的小鼠肺癌模型 发展CC，但这些模型不能再现CC在人类患者中的病理生理学和时间进程。 因此，我们的目标是开发和测试Kras驱动的小鼠肺癌模型，以便更准确地复制 为临床条件下便于确定发病机制提供实验依据 能够在更临床上测试药理学和支持性护理干预措施的系统 相关的时间框架。这项建议建立在我们对肺俱乐部细胞特异性KrasG12D的强劲初步结果的基础上 描述CC启动和进展的表型和时间过程的小鼠模型。基于我们的 初步数据，我们假设我们的KrasG12D肺腺癌模型更接近于 人类CC的表型和时间进程与类似Kras驱动的小鼠的病理生理学比较 该模型与常用的小鼠肺CC模型的快速时间进程相一致。要开发这种模式 并测试我们的假设，我们将使用基因工程小鼠模型和体外 由从这些动物发展而来的肿瘤器官以及骨骼肌和脂肪组成的模型 细胞培养。我们的研究结果将通过提供新的体内和体外模型来推动该领域的发展 研究CC的病理生理学，并测试治疗干预措施。总的来说，这些工具和知识 将有助于将基础科学发现转化为更有效的患者CC治疗方法。

PROJECT SUMMARY Cancer cachexia (CC) is characterized by unintentional weight loss secondary to adipose and skeletal muscle tissue wasting. It results from a complex interaction between the tumor and host, where tumor released factors reprogram peripheral organ and tissue metabolism to cause wasting. CC affects a majority of patients with lung, pancreatic, and gastrointestinal cancer, in addition to patients with other advanced stage cancers, and is associated with increased treatment-related toxicity, poor response to chemo- and immunotherapy and is estimated to cause ~20% of all cancer-related deaths. Lung cancer is the second most common cancer worldwide and the leading cause of cancer-related deaths. A majority of lung cancer patients exhibit signs of CC at diagnosis, with up to 75% experiencing tissue wasting during treatment. Oncogenic KRAS mutations increase the risk for CC and are found in many aggressive cancers that are prone to CC, including pancreatic, gastrointestinal and lung cancer. In fact, a large majority of lung adenocarcinomas show evidence for elevated Ras pathway activation (84%). Studies have described murine lung cancer models with mutated Kras that develop CC, but these models fail to reproduce the pathophysiology and time course of CC in human patients. Thus, our goal is to develop and test mouse Kras driven lung cancer models that more accurately reproduce the clinical condition to facilitate identification of pathoetiological mechanisms and to provide an experimental system that enables testing of pharmacological and supportive care interventions over a more clinically relevant time frame. This proposal builds on our strong preliminary results from lung club cell specific KrasG12D mouse models characterizing the phenotypes and time course of CC initiation and progression. Based on our preliminary data, we hypothesize that our KrasG12D lung adenocarcinoma model more closely mimics the pathophysiology of human CC in its phenotypes and time course compared to a similar Kras driven mouse model that aligns with the rapid time course of commonly used murine lung CC models. To develop this model and test our hypotheses, we will use a combination of genetically engineered mouse models and in vitro models consisting of tumor organoids developed from these animals, along with skeletal muscle and adipose cell cultures. Results from our studies will advance the field by providing novel in vivo and in vitro models to study the pathophysiology of CC and to test therapeutic interventions. Collectively, these tools and knowledge will inform translation of basic science discoveries into more effective treatments for CC in patients.