Project 2: Delta Stromal Ecology of NSCLC

项目2：NSCLC的Delta基质生态学

• 批准号: 10730406
• 负责人: Andriy Marusyk
• 金额: $ 48.15万
• 依托单位: H. LEE MOFFITT CANCER CTR & RES INST
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-15 至 2028-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10730406
• 关键词: Allografting; Birth; CRISPR library; Calibration; Cell Proliferation; Cells; Cessation of life; Combined Modality Therapy; DNA Sequence Alteration; Data Analyses; Development; Disease remission; Ecology; Ecosystem; Epidermal Growth Factor Receptor; Epigenetic Process; Evolution; Experimental Models; Failure; Genetic Programming; Guide RNA; Interdisciplinary Study; KRAS2 gene; Lentivirus Vector; Modeling; Molecular; Mus; Mutation; Non-Small-Cell Lung Carcinoma; Oncogenic; Outcome; Patients; Phenotype; Population; Probability; Proliferating; Property; Receptor Protein-Tyrosine Kinases; Relapse; Residual Neoplasm; Residual state; Resistance; Shapes; Shelter facility; Signal Transduction; Speed; System; Therapeutic; Therapeutic Intervention; Time; Vertebral column; Xenograft Model; Xenograft procedure; analysis pipeline; cancer therapy; digital pathology; experimental study; functional genomics; in silico; in vivo; inhibitor; insight; knowledge base; model development; mouse model; mutant; neoplastic; neoplastic cell; novel; novel strategies; paracrine; pharmacologic; resistance mechanism; resistance mutation; response; spatiotemporal; targeted treatment; tool; transcriptomics; translational approach; treatment optimization; tumor; tumor growth

Project 2 abstract Project 2 will investigate the changes in neoplastic and stromal compartments during the acquisition of resistance to ALK and KRAS targeting therapies, with specific emphasis on the therapy-sheltering impact of the stromal niche, observed in multiple experimental models. Despite the growing appreciation of the potential contribution of stromal on the sensitivity of tumor cells to targeted therapies, there are no established conceptual frameworks and experimental pipelines to account for this effect on evolving resistance. Confounding the challenge, acquired resistance cannot be understood just with before-after snapshot analyses, as the sensitivity of tumor cells to therapies, stroma-tumor ratio, and stromal composition and effect are dynamically changing over the course of treatment. To understand the Decology of acquired resistance we will perform system-level characterization of temporal and spatial phenotypic changes within the tumor and stromal compartments, including changes in proliferation/death and clonal dynamics. These changes will be captured in the formalism of in silico models through careful integration of experimental and modeling tools. The quality and utility of the models will be assessed by making experimentally testable predictions. Following calibration, the models will be used to find novel strategies for combination therapies that optimize long-term remission. Initial model development and calibration will be performed in a xenograft model of ALK+ NSCLC that has been the focus of our recent interdisciplinary studies. Subsequently, we will use the pipelines to gain an understanding of the eco-evolutionary dynamics of other xenograft and syngeneic models of ALK+ and KRASG12C NSCLC. These studies will help develop the robust knowledge base required for the development of novel and impactful translational strategies.

项目2摘要 项目 2 将研究在获取 对 ALK 和 KRAS 靶向治疗的耐药性，特别强调 在多个实验模型中观察到的基质生态位。尽管人们越来越认识到其潜力 基质对肿瘤细胞对靶向治疗的敏感性的贡献，目前尚无确定的证据 概念框架和实验流程来解释这种对不断演变的耐药性的影响。 混淆了挑战，获得性阻力不能仅通过前后快照来理解 分析，如肿瘤细胞对治疗的敏感性、基质-肿瘤比率以及基质成分和效果 在治疗过程中动态变化。为了理解获得性抵抗的生态学，我们 将对肿瘤内的时间和空间表型变化进行系统级表征， 基质区室，包括增殖/死亡和克隆动力学的变化。这些变化将 通过仔细整合实验和建模工具，以计算机模型的形式体现。 模型的质量和实用性将通过进行可实验测试的预测来评估。下列的 校准后，这些模型将用于寻找优化长期组合疗法的新策略 缓解。初始模型开发和校准将在 ALK+ NSCLC 异种移植模型中进行 这是我们最近跨学科研究的重点。随后，我们将使用管道来获得 了解 ALK+ 的其他异种移植和同基因模型的生态进化动力学 KRASG12C 非小细胞肺癌。这些研究将有助于开发开发所需的强大知识库 新颖且有影响力的翻译策略。