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: 10771549
• 负责人: Aria Vaishnavi
• 金额: $ 24.9万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-01 至 2026-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10771549
• 关键词: 3-Dimensional; Acceleration; Alleles; BRAF gene; CRISPR/Cas technology; Cancer Biology; Cancer Patient; Cell Line; Cells; Cessation of life; Clinic; Clinical; Complementary DNA; DNA Sequence Alteration; Disease; Disease Progression; Disease Resistance; Dominant-Negative Mutation; Drug resistance; EGFR gene; Epidermal Growth Factor Receptor; Experimental Models; Family member; Genetic; Genetic Transcription; Genetically Engineered Mouse; Goals; Heterogeneity; In Vitro; KRAS2 gene; KRASG12D; Lung; Lung Neoplasms; Maintenance; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Modeling; Molecular; Monitor; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; Organoids; Patients; Phosphotransferases; Population; Proliferating; Receptor Signaling; Refractory; Reporting; Research; Research Personnel; Residual Neoplasm; Resistance; Role; Signal Transduction; Structure; System; Technology; Testing; Therapeutic; Time; Treatment outcome; Tumor Burden; Tumor Markers; United States; War; Work; Xenograft Model; acquired drug resistance; cancer initiation; established cell line; gain of function; genome editing; improved; in vitro Model; in vivo; loss of function; molecular subtypes; molecular targeted therapies; mouse model; neoplastic cell; overexpression; patient derived xenograft model; patient stratification; personalized medicine; predictive marker; programs; recruit; response; scaffold; single-cell RNA sequencing; spatiotemporal; success; targeted biomarker; targeted treatment; treatment response; treatment strategy; tumor; tumor heterogeneity; tumor initiation; tumor progression; tumorigenesis

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.

抽象的 肺癌是癌症相关死亡的全球领导者，估计有140万 全球死亡人数每年在美国的死亡人数约为160,000人。治疗结果有所改善 近年来，我们最近了解到，根据存在的患者可以分为子集 其肿瘤中发生的特定基因突变。这些致癌突变可以作为预测性 生物标志物可以用某些特定的治疗剂靶向这些肿瘤。这种方法有所改善 患有某些致癌突变的患者的治疗选择，但不是大多数患者。最终， 即使是对靶向治疗剂的最佳反应也会产生戏剧性但短暂的反应。一个小 细胞的种群保持难治性和生存，包括所谓的最小残留疾病 （MRD）。 MRD提供了驱动耐药性的分子基础和根部 - 最紧急的临床之一 在针对癌症的战争中挣扎。 在此提案中，我着手了解WT EGFR或其他ERBB家庭成员在调节中的作用 致癌程序，对靶向疗法的敏感性以及肺的小鼠和类器官模型中的MRD 癌症。该项目中描述的工作将使我能够使用优雅的遗传系统将 在某些情况下 最常见的肺癌分子亚型。我还将能够定义EGFR损失的后果 在MRD上使用最先进的单细胞RNA测序技术。最终，这些的长期目标 分析是为了识别和理解驱动MRD和部署的分子机制 理性的，有针对性的多疗法策略，以根除恶性肺癌中的MRD。