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将调查在获取过程中肿瘤和基质室的变化 对碱和KRA的抗药性靶向疗法，具体强调了治疗的避免疗法的影响 在多个实验模型中观察到的基质生态位。尽管对潜力越来越欣赏 基质对肿瘤细胞对靶向疗法的敏感性的贡献，没有建立 概念框架和实验管道可以解释这种对不断发展的抗性的影响。 混淆挑战，仅在快照前就无法理解获得的抵抗 分析，作为肿瘤细胞对疗法，基质肿瘤比和基质组成的敏感性以及作用 在治疗过程中正在动态变化。要了解获得的抵抗的解剖学我们 将对肿瘤内的时间和空间表型变化执行系统级表征 基质室，包括增殖/死亡和克隆动力学的变化。这些更改将是 通过仔细整合实验和建模工具，以在计算机模型的形式主义中捕获。 模型的质量和效用将通过对实验测试的预测进行评估。下列的 校准，这些模型将用于寻找优化长期组合疗法的新型策略 缓解。初始模型开发和校准将在ALK+ NSCLC的异种移植模型中进行 这一直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 对其他异种移植物的生态进化动力学的理解和Alk+和 KRASG12C NSCLC。这些研究将有助于发展发展所需的强大知识库 新颖而有影响力的翻译策略。