BAY AREA & ANDERSON TEAM AGAINST ACQUIRED RESISTANCE - U54 PROGRAM (BAATAAR-UP)

海湾地区

• 批准号: 10517257
• 负责人: Trever G Bivona
• 金额: $ 111.92万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-30 至 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10517257
• 关键词: Address; Area; CD47 gene; Cancer Etiology; Cancer Patient; Cell Survival; Cells; Chronic; Clinical; Communities; Cues; Data Science Core; Data Set; Development; Disease; Drug resistance; Ecosystem; Ensure; Epidermal Growth Factor Receptor; Event; Extracellular Matrix; Fibroblasts; Foundations; Funding; Future; Geography; Goals; Human; Immune; Intercept; KRAS2 gene; Link; Lung; Macrophage Activation; Malignant Neoplasms; Malignant neoplasm of lung; Medicine; Methods; Modeling; Molecular; NF-kappa B; Nature; Non-Small-Cell Lung Carcinoma; Oncogenic; Organoids; PD-1/PD-L1; PDPK1 gene; Paracrine Communication; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmaceutical Preparations; Pre-Clinical Model; Process; Progress Reports; Proteomics; Public Health; Research; Research Project Grants; Resistance; Signal Transduction; Specimen; System; Testing; Therapeutic; acquired drug resistance; base; cancer cell; cancer therapy; cancer type; clinical translation; cytokine; data sharing; humanized mouse; immunosuppressive checkpoint; improved; improved outcome; innovation; macrophage; molecular targeted therapies; mortality; mouse model; mutant; neoplastic cell; patient derived xenograft model; precision oncology; prevent; programs; resistance mechanism; response; success; targeted treatment; therapeutic evaluation; therapy resistant; treatment strategy; tumor; tumor microenvironment; tumor progression; tumor xenograft

Project Summary/Abstract: The goal of this BAATAAR-UP renewal program application within the NCI ARTNet is to characterize the mechanisms of, and therapeutically counteract, acquired resistance to molecular therapies in non-small cell lung cancer (NSCLC) by delineating the tumor-tumor microenvironment (TME) ecosystem and its plasticity during treatment. Acquired resistance is defined as tumor progression that occurs during therapy and after an initial tumor response. The overarching hypothesis is that acquired resistance to molecular therapies can be thwarted by defining and exploiting vulnerabilities in the cellular, signaling, and geographic tumor ecosystem networks that allow tumors to survive and grow during therapy. In lung cancer and other cancer types, the use of targeted therapies that inhibit important and common oncogenic driver alterations such as mutant EGFR and KRAS (G12C) and block immunosuppressive checkpoints such as PD1/PDL1 is improving patient outcomes. A major challenge to transforming cancers into chronic or curable diseases is acquired resistance, which enables lethal cancer progression in patients. Understanding the mechanisms underlying acquired resistance is essential to develop counteracting strategies that improve patient survival. During the prior NCI U54 DRSC funding period, our team uncovered several mechanisms of acquired resistance to targeted therapy in human NSCLC by studying clinical specimens and innovative patient-derived models including humanized murine models bearing patient-derived xenografts (PDXs) and patient-derived organoids (PDOs) with an intact TME. Our expert team proposes to investigate these mechanisms, and identify others, synergistically and iteratively via 3 Research Projects and optimal interactions with 2 Cores. A Data Science Core will analyze, harmonize, centralize, and share data obtained across the basic and translational continuum using innovative methods. An Administrative Core will ensure optimal project integration and internal and external interactions with the ARTNet Consortium, and scientific and lay communities. Project 1 (Clinical tumor-TME acquired resistance) is translational and uses clinical specimens and patient-derived models to test the hypothesis that tumor macrophages and tumor fibroblasts promote acquired resistance via paracrine signaling interactions including cytokine, CD47, and extracellular matrix (ECM) cues sensed by cancer cells and converging on survival pathways such as YAP and NF-kB. Project 2 (PDX tumor-TME acquired resistance) is translational and uses humanized mouse models to test the hypothesis that an immune-suppressive TME and activation of macrophage and fibroblast signaling circuits that support tumor cell survival via PDK1, YAP, and NF-kB signaling promote acquired resistance. Project 3 (PDO tumor-TME acquired resistance) is basic and uses synthetic lethal and proteomic profiling in PDOs with a TME to test the hypothesis that signaling interactions involving the ECM, TROP2, and CD47 promote acquired resistance. Synergistic, iterative interactions to study these mechanisms across projects and systems will yield robust, translatable treatment strategies to counteract acquired resistance.

项目摘要/摘要：NCI ARTNET中此Baataar-Up续订计划申请的目标 是为了表征对分子疗法的耐药性和治疗性抵抗的机制 在非小细胞肺癌（NSCLC）中，通过描述肿瘤肿瘤微环境（TME）生态系统和 它在治疗过程中的可塑性。获得的抗性定义为治疗过程中发生的肿瘤进展 在最初的肿瘤反应之后。总体假设是获得了对分子疗法的耐药性 可以通过定义和利用细胞，信号和地理肿瘤中的漏洞来挫败 允许肿瘤在治疗过程中生存和生长的生态系统网络。在肺癌和其他癌症类型中， 使用抑制重要且常见的致癌驱动因素（例如突变体）的靶向疗法 EGFR和KRAS（G12C）和阻止免疫抑制检查点（例如PD1/PDL1）正在改善患者 结果。将癌症转化为慢性或可治愈疾病的主要挑战是获得的阻力， 这可以使患者的致命癌症进展。了解获得的机制 抵抗对于制定改善患者生存的策略至关重要。在先前的NCI期间 U54 DRSC资助期，我们的团队发现了对目标治疗的几种抗药性机制 在人类NSCLC中，通过研究临床标本和创新的患者衍生模型，包括人性化的模型 带有患者衍生异种移植物（PDXS）和患者衍生的类器官（PDOS）的鼠模型具有完整 TME。我们的专家团队建议调查这些机制，并以协同性和识别他人进行协同识别 通过3个研究项目进行迭代和与2个核心的最佳相互作用。数据科学核心将分析， 使用创新的基本和翻译连续性获得的协调，集中和共享数据获得的数据 方法。管理核心将确保最佳项目集成以及内部和外部互动 与Artnet联盟以及科学和外行社区。项目1（获得了临床肿瘤-TME 抗性）是转化的，使用临床标本和患者衍生的模型来检验以下假设。 肿瘤巨噬细胞和肿瘤成纤维细胞通过旁分泌信号传导促进获得的耐药性 包括细胞因子，CD47和细胞外基质（ECM）提示，并通过癌细胞感知并收敛生存 YAP和NF-KB等途径。项目2（PDX肿瘤-TME获得的阻力）是转化的，并且使用 人源化小鼠模型，以测试免疫抑制TME和巨噬细胞激活的假设 以及通过PDK1，YAP和NF-KB信号传导支持肿瘤细胞存活的成纤维细胞信号传导电路促进 获得的阻力。项目3（PDO肿瘤-TME获得的抗性）是基本的，并且使用合成致命和 用TME在PDO中进行蛋白质组学分析，以检验以下假设：涉及ECM的信号传导相互作用， trop2和CD47促进了获得的抗性。协同，迭代相互作用以研究这些机制 在整个项目和系统之间，将产生可抵消获得的抵抗力的强大，可翻译的治疗策略。