Identifying Metabolic Vulnerabilities in Lung Cancer

总体项目摘要 肺癌代谢缺陷的识别 肺癌是世界范围内癌症死亡的最常见原因。酪氨酸激酶抑制剂和 免疫疗法已被证明在一部分患者中有效;然而， 这种疾病尤其对于转移性疾病保持低水平。此外，小细胞肺癌（SCLC）患者 预后差，尤其是对小细胞肺癌的认识和鉴别诊断方面存在差距， 有效的治疗策略。我们在这个提案中的目标是了解关键驱动因素的潜在生物学 通过识别代谢脆弱性，最终可以作为单一药物或组合使用， 免疫疗法来治疗肺癌。我们将通过聘请专家来实现这一目标， 已经开发出在非小细胞（NSCLC）和小细胞（NSCLC）中具有共同分子特征的临床前模型 肺癌（SCLC）和尖端代谢组学。我们有一个积极和协作的小组， 每月提供由每个项目和核心领导人共同撰写的项目和手稿。此外，本发明还 我们的计划项目资助（PPG）团队位于莫菲特癌症中心，这是一个理想的地方，研究 肺癌的发病机制。佛罗里达在新诊断的肺癌患者方面排名全国第二。 莫菲特治疗了其中10%的病例。该项目由四个项目和四个核心组成。这些项目和核心 合作和协同作用，以实现四个目标：一。通过以下方法确定肺癌的代谢脆弱性： 具有共同分子特征的体内和离体模型的综合分析，包括p53， NRF 2/KEAP 1和MYC（项目#1，由弗洛雷斯博士领导，项目#2，由DeNicola博士领导，项目#3，由Dr. Cleveland和Haura，以及由Rodriguez博士领导并得到行政核心#1支持的项目#4， 由弗洛雷斯博士和Haura博士（临床前模型和病理学核心2）撰写，由Cress博士和Karreth博士（代谢）领导 核心#3，由Koomen博士领导，和数据科学核心#4，由弗里德利博士领导），ii.为了确定代谢 通过检查肿瘤微环境并获得与免疫疗法协同作用的脆弱性， 对髓源性抑制细胞（MDSC）的深入分子理解。（项目#4与 项目#1和#2以及核心#2），iii.建立小鼠模型作为了解代谢途径的平台 用于具有不同遗传特征的肺癌，并评估肺癌的治疗策略。 (Core#2支持项目#1 - 4），以及iv.在本地和全球范围内共享资源和数据， 肺癌代谢脆弱性的综合分子理解。(Core#4所有人的努力 项目和核心）。

OVERALL PROJECT SUMMARY IDENTIFYING METABOLIC VULNERABILITIES IN LUNG CANCER Lung Cancer is the most common cause of cancer deaths world-wide. Tyrosine kinase inhibitors and immunotherapy have been shown to be effective in a subset of patients; however, the overall survival rate for this disease remains low especially for metastatic disease. Moreover, small cell lung cancer (SCLC) patients have a poor prognosis, and there especially exists a gap in knowledge in understanding SCLC and identifying effective therapeutic strategies. Our goal in this proposal is to understand the underlying biology of key drivers in lung cancer by identifying metabolic vulnerabilities that can ultimately be used as single agents or combined with immunotherapy to target lung cancer therapeutically. We will achieve this goal by engaging experts that have developed preclinical models with common molecular signatures in non-small cell (NSCLC) and small cell lung cancer (SCLC) and cutting-edge metabolomics. We have an active and collaborative group that meets twice monthly with projects and manuscripts that are co-authored by the leaders of each project and core. Additionally, our Program Project Grant (PPG) team is located at Moffitt Cancer Center, which is an ideal place to study the pathogenesis of lung cancer. Florida is number 2 in the country in terms of newly diagnosed lung cancer patients. Moffitt treats 10% of these cases. The PPG consists of four projects and four cores. These projects and cores collaborate and synergize to meet four objectives: i. To identify metabolic vulnerabilities in lung cancers through integrative analysis of in vivo and ex vivo models with common molecular signatures, including p53, NRF2/KEAP1, and MYC (Project #1, led by Dr. Flores, Project #2, led by Dr. DeNicola, Project #3, led by Drs. Cleveland and Haura, and Project #4, led by Dr. Rodriguez with support from the Administrative Core #1, led by Drs. Flores and Haura, Preclinical Models and Pathology Core #2, led by Drs. Cress and Karreth, Metabolism Core #3, led by Dr. Koomen, and Data Science Core #4, led by Dr. Fridley), ii. To identify metabolic vulnerabilities that synergize with immunotherapy through examining the tumor microenvironment and gaining a deep molecular understanding of myeloid derived suppressor cells (MDSCs). (Project #4 in collaboration with Projects #1 and #2 and Core #2), iii. To build mouse models as a platform to understand the metabolic pathways utilized by lung cancers with different genetic signatures and to assess therapeutic strategies for lung cancer. (Core #2 supporting Projects #1-4), and iv. To share resources and data locally and globally to obtain an integrated molecular understanding of metabolic vulnerabilities in lung cancer. (Core #4 leading efforts from All Projects and Cores).