Uncovering the Biology of Resistance to Tyrosine Kinase Inhibitors in EGFR Mutant Lung Cancer Patient-Derived Models.

揭示 EGFR 突变肺癌患者衍生模型中酪氨酸激酶抑制剂耐药性的生物学。

基本信息

批准号：
9920134
负责人：
Don X Nguyen
金额：
$ 79.81万
依托单位：
YALE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-23 至 2024-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9920134
关键词：
3-Dimensional Address Affect Area Biological Biology Biopsy Brain Bypass Cancer Biology Cancer Etiology Cancer Model Cancer Patient Cell Line Cells Cessation of life Clinical Data Development Disease Disseminated Malignant Neoplasm Drug resistance Epidermal Growth Factor Receptor Erlotinib Evolution Exhibits Extracellular Matrix Gefitinib Generations Heterogeneity Histologic Human Immunotherapy Implant Knowledge Lead Light Link Liver Location Lung Adenocarcinoma Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of thorax Measures Mediator of activation protein Modeling Molecular Molecular Profiling Mutation Nature Neoplasm Metastasis Organoids Outcome Pathway interactions Patients Pattern Pharmacology Phenotype Play Pre-Clinical Model Principal Investigator Process Property Refractory Regimen Relapse Research Resistance Resources Role Sampling Series Signal Pathway Site Source Specimen Testing Tissues Tyrosine Kinase Inhibitor Xenograft procedure base cancer cell insight interdisciplinary approach molecular targeted therapies mutant neoplastic cell novel novel therapeutic intervention novel therapeutics patient subsets prevent programs resistance mechanism response subcutaneous targeted treatment therapy resistant translational research program tumor tumor microenvironment tumor xenograft

项目摘要

PROJECT SUMMARY A long-standing clinical observation is that metastatic cancers are refractory to treatment. Even with the advent of molecularly targeted therapies, drug resistance almost always emerges and patients ultimately succumb to further metastatic spread of the cancer. In the case of EGFR mutant lung adenocarcinoma (LUAD), tumors can acquire resistance to tyrosine kinase inhibitors (TKI) while spreading to the liver and brain. The mechanisms linking these morbid outcomes remain poorly understood. Here, we propose to study the biological properties of EGFR mutant tumors as they evolve through TKI treatment, identify the factors that allow treated tumor cells to persist and how features of the metastatic niche and depth (or durability) of responses to TKIs are linked. We hypothesize that, 1) the tumor microenvironment (TME) and tumor cell extrinsic factors are critical determinants of disseminated tumor cell persistence following TKI treatment and 2) that the reliance on these factors decreases in highly resistant metastasis through sequential TKI treatment. To study this hypothesis, we have successfully established a repeat biopsy program to collect and analyze lung cancer specimens, including EGFR mutant LUADs before and after TKI treatment. Through this program we have established >20 patient-derived models of EGFR mutant LUAD, including organoid cultures and subcutaneous and orthotopic patient-derived xenografts (PDXs). In Aim 1, we will generate additional patient- derived models of cancer (PDMCs) as organoids, subcutaneous or orthotopic PDXs, collected from 10 patients with EGFR mutant LUAD longitudinally prior to TKI treatment and at acquired resistance to TKIs. These PDMCs will be genomically and histologically characterized, while their TKI sensitivity will be compared to the patient specimens. In Aim 2, we will leverage these models to determine the mechanisms by which TKI resistance affects the aggressiveness of EGFR mutant tumors. Using paired pre- and post-TKI PDMCs, we will evaluate the latency and site of relapse of these tumors. We will also determine how known mechanisms of TKI resistance affect the metastatic properties of EGFR mutant tumors and identify novel dual molecular mediators of resistance and metastasis. Finally, in Aim3, we will Identify tissue-specific determinants of tumor cell persistence following TKI treatment. Focusing on tumors that we know are responsive to specific TKIs, we will establish whether tumors implanted in different sites of metastases exhibit different sensitivity to TKIs and identify the cellular, molecular and pharmacological determinants of these differences. We will test the mechanistic prediction that the stromal extracellular matrix modulates the ability of tumor cells to persist upon TKI treatment. Thoracic malignancies account for most cancer-related deaths. By integrating the complementary expertise and resources of 2 principal investigators and collaborators, our aims will provide fundamental insights into the longitudinal evolution of EGFR mutant LUAD under treatment and the mechanistic relationship between drug resistance and the tumor microenvironment, which will lead to new therapeutic strategies for metastatic cancers.

项目概要长期的临床观察表明，转移性癌症难以治疗。即使来临在分子靶向治疗中，几乎总是会出现耐药性，患者最终会死于癌症进一步转移扩散。对于 EGFR 突变型肺腺癌 (LUAD)，肿瘤可以获得对酪氨酸激酶抑制剂（TKI）的耐药性，同时扩散到肝脏和大脑。机制这些病态结果之间的联系仍然知之甚少。在这里，我们建议研究生物特性 EGFR 突变肿瘤通过 TKI 治疗演变，确定允许治疗的肿瘤细胞发生变化的因素持续存在以及转移生态位的特征与 TKI 反应的深度（或持久性）如何相关。我们假设，1）肿瘤微环境（TME）和肿瘤细胞外在因素是关键的决定因素 TKI 治疗后播散性肿瘤细胞持续存在的影响以及 2) 对这些因素的依赖减少通过序贯 TKI 治疗的高耐药转移。为了研究这一假设，我们成功建立了重复活检计划来收集和分析肺癌标本，包括 TKI 治疗前后的 EGFR 突变 LUAD。通过这个计划我们已建立超过 20 个源自患者的 EGFR 突变体 LUAD 模型，包括类器官培养物和皮下和原位患者来源的异种移植物（PDX）。在目标 1 中，我们将产生额外的患者- 从 10 名患者收集的类器官、皮下或原位 PDX 等癌症衍生模型 (PDMC) 在 TKI 治疗前和获得 TKI 耐药时纵向使用 EGFR 突变体 LUAD。这些 PDMC 将进行基因组学和组织学表征，同时将其 TKI 敏感性与患者进行比较标本。在目标 2 中，我们将利用这些模型来确定 TKI 耐药性影响的机制 EGFR突变肿瘤的侵袭性。使用配对的 TKI 前后 PDMC，我们将评估延迟以及这些肿瘤的复发部位。我们还将确定已知的 TKI 耐药机制如何影响 EGFR 突变肿瘤的转移特性，并鉴定新的耐药和耐药双分子介质转移。最后，在目标 3 中，我们将确定 TKI 后肿瘤细胞持久性的组织特异性决定因素治疗。重点关注我们已知对特定 TKI 有反应的肿瘤，我们将确定肿瘤是否植入不同部位的转移瘤对 TKI 表现出不同的敏感性，并识别细胞、分子以及这些差异的药理学决定因素。我们将测试基质的机械预测细胞外基质调节肿瘤细胞在 TKI 治疗后持续存在的能力。胸部恶性肿瘤占大多数癌症相关死亡的原因。通过整合互补的专业知识以及 2 位主要研究人员和合作者的资源，我们的目标将为治疗中EGFR突变体LUAD的纵向进化及药物之间的机制关系耐药性和肿瘤微环境，这将导致转移性癌症的新治疗策略。