Clinical specimen tumor-TME acquired resistance

临床标本肿瘤-TME获得性耐药

• 批准号: 10517260
• 负责人: Trever G Bivona
• 金额: $ 35.72万
• 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/10517260
• 关键词: Antitumor Response; Automobile Driving; CD44 gene; CD47 gene; CSF1 gene; Cancer Etiology; Cell Communication; Cell Survival; Cells; Chronic; Clinical; Clinical Treatment; Coupled; Drug Tolerance; Ecosystem; Epidermal Growth Factor Receptor; Evolution; Extracellular Matrix; Fibroblasts; Funding; Future; Genetic; Goals; Heterogeneity; Immune; Integrins; KRAS2 gene; Knowledge; Ligands; Malignant Neoplasms; Mediating; Migration Inhibitory Factor; Modeling; Molecular; Non-Small-Cell Lung Carcinoma; Oncogenes; Oncogenic; PDGFRB gene; PTK2 gene; Paracrine Communication; Pathway interactions; Patient-Focused Outcomes; Patients; Pharmacology; Phenotype; Platelet-Derived Growth Factor; Proteomics; Research Project Grants; Residual Tumors; Resistance; Role; Signal Transduction; Specimen; Therapeutic; Work; base; biomarker-driven; cancer cell; cancer subtypes; cell type; clinical translation; combat; cytokine; immunosuppressive checkpoint; improved; improved outcome; inhibitor; innovation; insight; macrophage; molecular targeted therapies; mortality; mutant; neoplastic cell; paracrine; programmed cell death protein 1; programs; resistance mechanism; response; spatial relationship; targeted agent; therapeutic target; translational approach; translational goal; treatment response; tumor; tumor microenvironment; tumor progression

Project Summary/Abstract: The goal of this translational Project within BAATAAR-UP 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 (AR) is defined as tumor progression that occurs during active therapy and after an initial therapy response. The overarching hypothesis is that AR can be therapeutically counteracted by defining the cellular and signaling networks allowing tumors to survive and grow during therapy. The use of molecularly targeted therapies that inhibit oncogenic driver alterations such as mutant EGFR and KRAS and block immunosuppressive checkpoints such as PD1/L1 is improving outcomes for patients with aggressive tumors including NSCLC, which nonetheless remains the leading cause of cancer mortality. Despite profound progress, a major challenge to transforming NSCLC into a chronic or curable cancer is AR that enables lethal tumor progression in patients. Understanding the mechanisms driving AR is essential to develop strategies to counteract it and induce sustained anti-tumor responses to improve patient survival. Critical knowledge gaps are whether and how tumor cell/TME cell interactions and spatial relationships promote AR. Another aspect of the evolution of AR that is poorly defined is the basis of the incomplete response and residual disease that is typical during therapy. This residual disease contains drug tolerant cancer cells and interactive TME cells that evolve together to promote the aggressive transition into AR. Defining how this transition occurs could provide strategies to thwart it. Our work accomplished during the prior U54 funding period showed that oncogene-driven NSCLCs contain a rich cellular ecosystem that evolves during molecular treatments (e.g., EGFR, ALK, and RAS pathway targeted agents). We discovered heterogeneity and plasticity in tumor cells and TME cells, including immune and non-immune cell types, and spatial relationships at different clinical treatment states including at AR that we hypothesize contribute collectively to AR. These include bi-directional interactions between tumor macrophages and cancer cells and tumor fibroblasts and cancer cells via discrete signaling circuits that promote cancer cell survival and remodel the TME into a more pro-tumor phenotype at AR. Examples include cytokine (CSF1, TNFa, IL1b), and CD47 signaling between tumor macrophages and cancer cells and macrophage migration inhibitory factor (MIF)-CD74/CD44 and extracellular matrix (ECM)/integrin signaling between tumor fibroblasts and cancer cells at AR. Our goal is to define and therapeutically target these, and additional, cancer cell and TME cell networks to therapeutically thwart AR. We focus on clinically important and prevalent NSCLC subtypes defined by oncogenic mutant EGFR and KRAS and current clinical targeted inhibitors against these major oncogenic drivers. Two Specific Aims are proposed. Our work will highlight mechanisms driving AR across the tumor-TME continuum in EGFR- and KRAS-driven NSCLCs and identify counteracting therapeutic strategies for translation.

项目摘要/摘要：Baataar-Up中此翻译项目的目标是表征 在非小细胞肺中对分子疗法的耐药性和治疗方法的机理 癌症（NSCLC）通过描述肿瘤肿瘤微环境（TME）生态系统及其在期间的可塑性 治疗。获得的耐药性（AR）被定义为在主动治疗期间和之后发生的肿瘤进展 初始疗法反应。总体假设是AR可以通过治疗作用。 定义细胞和信号网络，允许肿瘤在治疗过程中生存和生长。使用 分子靶向疗法抑制致癌驱动力改变，例如突变EGFR和KRAS， 阻止免疫抑制检查点，例如PD1/L1，正在改善侵略性患者的结局 包括NSCLC在内的肿瘤仍然是癌症死亡率的主要原因。尽管深刻 进步是将NSCLC转化为慢性或可治愈的癌症的主要挑战是AR，可以致命 患者的肿瘤进展。了解驱动AR的机制对于制定策略至关重要 抵消它并诱导持续的抗肿瘤反应以改善患者的生存率。关键的知识差距是 肿瘤细胞/TME细胞相互作用和空间关系是否促进AR。的另一个方面 AR的演变定义不明是不完全反应和典型的残留疾病的基础 在治疗期间。这种残留疾病含有耐药的癌细胞和相互作用的TME细胞，这些细胞进化 共同促进积极向AR的过渡。定义这种过渡的发生如何提供策略 挫败它。我们在以前的U54资金期间完成的工作表明，致癌基因驱动的NSCLCS 包含一个丰富的细胞生态系统，该生态系统在分子处理过程中演变（例如EGFR，ALK和RAS途径 目标代理）。我们在肿瘤细胞和TME细胞中发现了异质性和可塑性，包括免疫 和非免疫细胞类型以及不同临床治疗状态的空间关系，包括在AR处 假设为AR共同贡献。这些包括肿瘤巨噬细胞之间的双向相互作用 癌细胞以及肿瘤成纤维细胞和癌细胞通过促进癌细胞的离散信号传导电路 生存并重塑TME在AR处的更亲肿瘤的表型。例子包括细胞因子（CSF1，TNFA，， IL1b）和CD47肿瘤巨噬细胞和癌细胞之间的信号传导以及巨噬细胞迁移抑制 因子（MIF）-CD74/CD44和细胞外基质（ECM）/整联蛋白信号在肿瘤成纤维细胞和癌症之间 AR的细胞。我们的目标是定义和靶向这些，以及其他癌细胞和TME细胞 网络以挫败AR。我们专注于定义的临床重要和普遍的NSCLC子类型 通过致癌突变体EGFR和KRAS以及当前针对这些主要致癌性的临床靶向抑制剂 司机。提出了两个具体目标。我们的工作将突出驱动AR穿过肿瘤-TME的机制 EGFR和KRAS驱动的NSCLC中的连续体，并确定翻译的治疗策略。