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.

项目概要/摘要：在NCI ARTNet中申请BAATAAR-UP更新计划的目标 是描述对分子疗法的获得性耐药性的机制， 通过描绘肿瘤-肿瘤微环境（TME）生态系统， 在治疗过程中的可塑性。获得性耐药定义为治疗期间发生的肿瘤进展 以及在最初的肿瘤反应之后。最重要的假设是，对分子疗法的获得性耐药性 可以通过定义和利用细胞，信号和地理肿瘤中的漏洞来阻止 让肿瘤在治疗过程中存活和生长的生态系统网络。在肺癌和其他癌症类型中， 使用靶向疗法抑制重要和常见的致癌驱动改变， EGFR和KRAS（G12 C）和阻断免疫抑制检查点（如PD 1/PDL 1）正在改善患者 结果。将癌症转化为慢性或可治愈疾病的一个主要挑战是获得性耐药性， 这会导致患者发生致命的癌症进展。了解获得性免疫缺陷的机制 耐药性对于开发提高患者存活率的对抗策略至关重要。在NCI之前， U 54 DRSC资助期间，我们的团队发现了几种对靶向治疗获得性耐药的机制 通过研究临床标本和创新的患者源性模型，包括人源化 携带患者来源的异种移植物（PDX）和患者来源的类器官（PDO）的小鼠模型， TME。我们的专家小组建议调查这些机制，并确定其他机制，协同和 通过3个研究项目和2个核心的最佳交互迭代。数据科学核心将分析， 协调、集中和共享使用创新技术在基础和转换连续体中获得的数据， 方法.一个行政核心将确保最佳的项目整合以及内部和外部互动 与ARTNet联盟，科学界和非专业团体合作。项目1（临床肿瘤-TME获得 耐药性）是转化的，并使用临床标本和患者来源的模型来检验假设， 肿瘤巨噬细胞和肿瘤成纤维细胞通过旁分泌信号相互作用促进获得性抗性 包括细胞因子、CD 47和细胞外基质（ECM）信号，这些信号被癌细胞感知并聚集在存活率上 途径如雅普和NF-kB。项目2（PDX肿瘤-TME获得性耐药性）是翻译性的， 人源化小鼠模型来测试免疫抑制性TME和巨噬细胞活化的假设 通过PDK 1、雅普和NF-κ B信号通路支持肿瘤细胞存活的成纤维细胞信号通路促进 获得性抵抗项目3（PDO肿瘤-TME获得性耐药性）是基本的，并使用合成致死和 在具有TME的PDO中进行蛋白质组分析以检验涉及ECM的信号相互作用的假设， TROP 2和CD 47促进获得性抗性。协同，迭代的相互作用来研究这些机制 跨项目和系统的研究将产生强大的、可转化的治疗战略，以抵消获得性耐药性。