Systems Biochemistry in Lung Cancer: Toward a Mechanistic Understanding of NSCLC

描述（由申请人提供）：肺癌的死亡率是北美和其他地区所有癌症中最高的，并且由于潜伏期长，在可预见的未来可能仍将如此。此外，虽然I期肺癌的5年生存率为60-70%，但晚期疾病预后非常差。在有危险的个体中准确检测无症状早期肺癌目前是不可靠的。更好地了解肺癌的基本生物化学是基于机制的可靠的疾病早期检测和改进治疗方法的先决条件。转化细胞的复杂性，以及宿主与肿瘤之间多变的相互作用，使得任何单一的方法都难以解决这个问题。在实验室、小鼠模型和人类受试者的机制水平上研究肺癌的系统生物化学方法为解决癌症发展和进展的复杂性提供了机会。稳定同位素分解代谢组学的使用为肺癌提供了必要的直接生化信息，并且处理最少，否则无法获得。该计划将以以下综合项目为基础，以三管齐下的方式解决问题：项目1：细胞系统生物化学。肺癌细胞的微环境营养可利用性和免疫调节。项目2;临床前系统生物化学。应用SIRM在人非小细胞肺癌异种移植小鼠中研究免疫调节剂-葡聚糖的生化机制。

DESCRIPTION (provided by applicant): Deaths from lung cancer are the highest of all cancers in North America and elsewhere and, because of the long incubation time, are likely to remain so for the foreseeable future. Furthermore, although the 5-year survival rate of stage I lung cancer is 60-70%, later stage disease has a very poor prognosis. Accurate detection of asymptomatic early stage lung cancer in individuals at risk is currently unreliable. A better understanding of the basic biochemistry of lung cancers is a prerequisite to mechanism-based reliable early detection of the disease, and to improved approaches to treatment. The very complexity of the transformed cells, and the variable host-tumor interactions, makes the problem refractory to any single approach. A systems biochemistry approach in which lung cancers are studied at the mechanistic level in the laboratory, in mouse models and in human subjects offers the opportunity to address the complexity of cancer development and progression. The use of stable isotope resolved metabolomics provides the necessary direct biochemical information about lung cancer with minimal processing that is not otherwise available. This program will address the problem in a 3-pronged approach, based on the following integrated projects: Project 1: Cellular Systems Biochemistry. Microenvironmental nutrient availability and immune modulation in lung cancer cells. Project 2; Preclinical Systems Biochemistry. Using SIRM in Human NSCLC xenograft mouse to determine biochemical mechanisms of immunomodulator ¿-glucan. Project 3: Translational Systems Biochemistry. Molecular mechanisms of NSCLC and response to ¿-glucan by SIRM. The three projects will use a common mechanistic approach to understanding cancer biochemistry namely stable isotope resolved metabolomics (SIRM) that we have been developing over the last eight years. The analytical requirements will be met in the SIRM Analytical Core, which also supplies the necessary sample handling and bioinformatics support for the three projects. Core A provides overall administrative support.