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.

项目概要/摘要：BAATAAR-UP中的这个翻译项目的目标是描述 非小细胞肺癌中对分子疗法的获得性耐药性的机制和治疗性抵消 通过描绘肿瘤-肿瘤微环境（TME）生态系统及其在治疗过程中的可塑性， 治疗获得性耐药（AR）定义为在积极治疗期间和治疗后发生的肿瘤进展。 初步治疗反应。总体假设是，AR可以通过以下方式在治疗上抵消： 定义了允许肿瘤在治疗期间存活和生长的细胞和信号网络。使用 抑制致癌驱动改变如突变EGFR和KRAS的分子靶向疗法， 阻断免疫抑制检查点（如PD1/L1）可改善侵袭性乳腺癌患者的预后。 包括非小细胞肺癌（NSCLC）在内的多种肿瘤中，肺癌仍然是癌症死亡率的主要原因。尽管深刻 随着研究的进展，将NSCLC转化为慢性或可治愈癌症的主要挑战是AR，其使致命的 患者的肿瘤进展。了解驱动AR的机制对于制定战略至关重要， 中和它并诱导持续的抗肿瘤反应以提高患者的存活率。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以及如何促进AR。的另一方面 定义不明确的AR演变是典型的不完全缓解和残留疾病的基础 在治疗期间。这种残留疾病包含耐药癌细胞和相互作用的TME细胞， 共同推动向AR的积极过渡。定义这种转变如何发生可以提供战略 我们在之前的U54资助期间完成的工作表明，癌基因驱动的NSCLC 包含在分子治疗期间进化的丰富的细胞生态系统（例如，EGFR、ALK和RAS通路 目标代理商）。我们发现了肿瘤细胞和TME细胞的异质性和可塑性，包括免疫 和非免疫细胞类型，以及不同临床治疗状态下的空间关系，包括我们认为 假设共同促成了AR。这些包括肿瘤巨噬细胞之间的双向相互作用 以及癌细胞、肿瘤成纤维细胞和癌细胞通过离散的信号传导回路， 存活并将TME重塑为AR时更促肿瘤表型。实例包括细胞因子（CSF 1，TNF α， IL 1b）和肿瘤巨噬细胞与癌细胞之间的CD47信号传导以及巨噬细胞迁移抑制 肿瘤成纤维细胞和癌症之间的因子（MIF）-CD74/CD44和细胞外基质（ECM）/整合素信号传导 细胞在AR我们的目标是定义和治疗靶向这些，以及额外的癌细胞和TME细胞 网络来治疗性地阻止AR。我们专注于临床重要和流行的NSCLC亚型定义 致癌突变EGFR和KRAS以及目前针对这些主要致癌突变的临床靶向抑制剂 司机提出了两个具体目标。我们的工作将强调驱动AR穿过肿瘤的机制-TME EGFR和KRAS驱动的NSCLC中的连续体，并确定用于翻译的抵消治疗策略。