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

开发临床相关的肺癌恶病质小鼠模型以研究病理学和治疗策略

• 批准号: 10729653
• 负责人: MICHAEL J TOTH
• 金额: $ 21.88万
• 依托单位: UNIVERSITY OF VERMONT & ST AGRIC COLLEGE
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-04 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10729653
• 关键词: Address; Adipocytes; Adipose tissue; Affect; Animal Model; Animals; Basic Science; Body Weight decreased; Cancer Etiology; Cancer Model; Cancer Patient; Cell Culture Techniques; Cells; Cessation of life; Clinical; Complex; Data; Development; Diagnosis; Drug resistance; Enzymes; Event; Exhibits; Functional disorder; Genetically Engineered Mouse; Goals; Growth; Human; Immunotherapy; In Vitro; Intervention; K-ras mouse model; KRAS oncogenesis; Knowledge; Lipase; Lipolysis; Low Prevalence; Lung; Lung Adenocarcinoma; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of lung; Malignant neoplasm of pancreas; Metabolic; Metabolic Pathway; Metabolism; Modeling; Mus; Muscle; Muscle Cells; Muscle Fibers; Mutate; Mutation; Neoplasm Metastasis; Organ; Organoids; Pancreas; Pathway interactions; Patients; Peripheral; Phenotype; Pre-Clinical Model; Prevalence; Prevention; Risk; Role; Secondary to; Skeletal Muscle; Supportive care; Syndrome; System; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Toxic effect; Translating; Translations; Treatment-Related Cancer; Treatment-related toxicity; Tumor Burden; Tumor-Derived; adverse outcome; animal data; cancer cachexia; cancer risk; cancer therapy; cancer type; clinically relevant; design; effective therapy; experience; fat wasting; gastrointestinal; in vitro Model; in vivo; inhibitor; mortality; mouse model; novel; novel therapeutic intervention; pharmacologic; programs; release factor; response; side effect; skeletal muscle wasting; therapeutic evaluation; therapeutic target; tool; transcriptomics; tumor; tumor growth; tumor progression; wasting

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.

项目摘要 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与宿主之间复杂的相互作用的结果， 因子重新编程外周器官和组织代谢以引起消耗。CC影响大多数患者 患有肺癌、胰腺癌和胃肠道癌的患者，以及患有其他晚期癌症的患者， 并且与增加的治疗相关毒性、对化疗和免疫治疗的不良反应以及 据估计约占所有癌症相关死亡的20%。肺癌是第二常见的癌症 是全球范围内癌症相关死亡的主要原因。大多数肺癌患者表现出以下症状： 诊断时为CC，高达75%的患者在治疗期间出现组织浪费。致癌性KRAS突变 增加患CC的风险，并在许多易患CC的侵袭性癌症中发现，包括胰腺癌， 胃肠癌和肺癌。事实上，大多数肺腺癌显示出升高的 Ras通路激活（84%）。研究已经描述了具有突变的Kras的鼠肺癌模型， 发展CC，但这些模型不能再现人类患者中CC的病理生理学和时程。 因此，我们的目标是开发和测试小鼠Kras驱动的肺癌模型， 临床状况，以促进病理病因学机制的鉴定，并提供一个实验 该系统能够测试药理学和支持性护理干预措施，而不是临床上的 相关的时间框架。该建议建立在我们从肺俱乐部细胞特异性KrasG12D获得的强有力的初步结果的基础上 小鼠模型表征CC起始和进展的表型和时程。基于我们 根据初步数据，我们假设我们的KrasG12D肺腺癌模型更接近于模拟 人CC在其表型和时间过程中的病理生理学与类似的Kras驱动小鼠相比 该模型与常用的鼠肺CC模型的快速时间过程一致。为了开发这个模型 为了验证我们的假设，我们将使用基因工程小鼠模型和体外实验相结合的方法， 由这些动物产生的肿瘤类器官组成的模型，沿着骨骼肌和脂肪 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进该领域， 研究CC的病理生理学并测试治疗干预。这些工具和知识 将为基础科学发现转化为更有效的CC患者治疗提供信息。