Elucidating the role of support signaling in promoting minimal residual disease in mouse models of oncogene-driven lung cancer

阐明支持信号传导在促进癌基因驱动肺癌小鼠模型中微小残留病中的作用

• 批准号: 10504719
• 负责人: Aria Vaishnavi
• 金额: $ 11.57万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-11-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10504719
• 关键词: Cells; Cessation of life; Clinical; DNA Sequence Alteration; Drug resistance; EGFR gene; Epidermal Growth Factor Receptor; Experimental Models; Family member; Genetic; Goals; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Modeling; Molecular; Mus; Mutation; Oncogenes; Oncogenic; Organoids; Patients; Plant Roots; Population; Refractory; Residual Neoplasm; Role; Signal Transduction; System; Technology; Therapeutic; Treatment outcome; Tumor Markers; United States; War; Work; base; improved; molecular subtypes; mouse model; predictive marker; programs; response; single-cell RNA sequencing; targeted treatment; tumor; tumor progression

ABSTRACT Lung cancer is the global leader in cancer related deaths, and responsible for an estimated 1.4 million deaths worldwide and ~160,000 deaths in the United States annually. Treatment outcomes have improved in recent years with our recent understanding that patients can be divided into subsets based on the presence of specific genetic mutations that occur in their tumors. These oncogenic mutations can serve as predictive biomarkers that these tumors can be targeted with certain specific therapeutics. This approach has improved therapeutic options for patient with certain oncogenic mutations, but not the majority of patients. Ultimately, even the best responses to targeted therapeutics result in dramatic, but transient responses. A small population of cells remain refractory and survive, comprising what is known as minimal residual disease (MRD). MRD provides the molecular basis and roots that drive drug resistance - one of the most urgent clinical struggles in the war against cancer. In this proposal I set out to understand the role of WT EGFR or other ERBB family members in modulating oncogenic programs, the sensitivity to targeted therapies, and MRD in mouse and organoid models of lung cancer. The work described in this project will allow me to use elegant genetic systems to separate out the distinct role and contributions for WT EGFR from other ERBB family members in the context of some of the most common molecular subtypes of lung cancer. I will also be able to define the consequences of EGFR loss on MRD using state-of-the-art single cell RNA-sequencing technologies. Ultimately, the long-term goal of these analyses is to identify and understand the molecular mechanisms that drive MRD and the deployment of rational, targeted polytherapy strategies to eradicate MRD in malignant lung cancers.

摘要 肺癌是全球癌症相关死亡的主要原因，估计有140万人死于肺癌。 全世界每年约有160，000人死亡，美国每年约有160，000人死亡。治疗结果有所改善， 近年来，随着我们最近的理解，患者可以根据是否存在 肿瘤中发生的特定基因突变。这些致癌突变可以作为预测 生物标志物表明这些肿瘤可以用某些特定的治疗方法靶向。这一做法得到了改善 对于某些致癌突变的患者，但不是大多数患者的治疗选择。最后， 即使是对靶向治疗的最佳反应也会导致显著但短暂的反应。一个小 一群细胞保持难治性并存活，包括所谓的微小残留病 （MRD）。MRD提供了驱动耐药性的分子基础和根源-最紧迫的临床研究之一 在与癌症的斗争中。 在本提案中，我着手了解WT EGFR或其他ERBB家族成员在调节中的作用 致癌程序，对靶向治疗的敏感性，以及小鼠和肺类器官模型中的MRD 癌在这个项目中描述的工作将允许我使用优雅的遗传系统来分离出 WT EGFR与其他ERBB家族成员在某些疾病背景下的不同作用和贡献 肺癌最常见的分子亚型。我也将能够定义EGFR丢失的后果 使用最先进的单细胞RNA测序技术进行MRD。最终，这些长期目标 分析的目的是识别和理解驱动MRD和部署的分子机制。 合理的，有针对性的多药治疗策略，以消除恶性肺癌的MRD。