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.

项目摘要长期以来的临床观察是，转移性癌症对治疗是难治性的。即使有降临在分子靶向疗法中，耐药性几乎总是出现，患者最终屈服于癌症的进一步转移扩散。对于EGFR突变肺腺癌（LUAD），肿瘤可以在扩散到肝脏和大脑时，获得对酪氨酸激酶抑制剂（TKI）的耐药性。机制将这些病态结果联系起来仍然知之甚少。在这里，我们建议研究 EGFR突变肿瘤通过TKI治疗进化，确定允许治疗肿瘤细胞的因素持续以及如何将转移性利基和深度（或持久性）的特征联系起来。我们假设，1）肿瘤微环境（TME）和肿瘤细胞外部因素是关键的决定因素 TKI治疗后的传播肿瘤细胞持久性和2）对这些因素的依赖降低通过顺序TKI处理，在高度抗性转移中。为了研究这一假设，我们成功建立了一个重复的活检计划来收集和分析肺癌标本，包括TKI治疗前后的EGFR突变体。通过这个程序，我们已经建立了> 20种患者衍生的EGFR突变体LUAD模型，包括器官培养物和皮下和原位患者衍生的异种移植物（PDXS）。在AIM 1中，我们将产生额外的患者 - 从10例患者中收集的癌症（PDMC）的癌症模型（PDMC）作为皮下或原位PDXS 在TKI处理前纵向使用EGFR突变体Luad，并获得对TKI的耐药性。这些PDMC 将在基因组和组织学上具有特征，而其TKI敏感性将与患者进行比较标本。在AIM 2中，我们将利用这些模型来确定TKI抗性影响的机制 EGFR突变肿瘤的侵略性。使用配对的前和TKI PDMC，我们将评估延迟和这些肿瘤复发部位。我们还将确定TKI抗性的已知机制如何影响 EGFR突变肿瘤的转移特性，并鉴定出抗性的新型双分子介质和转移。最后，在AIM3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。专注于我们知道对特定TKI有反应的肿瘤，我们将确定肿瘤是否是否植入在不同位点的转移酶中表现出对TKI的敏感性不同，并鉴定了细胞，分子以及这些差异的药理决定因素。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。胸腔恶性肿瘤是大多数与癌症有关的死亡。通过整合补充专业知识以及2位首席研究人员和合作者的资源，我们的目标将提供基本的见解 EGFR突变体在处理下的纵向演变和药物之间的机械关系抗性和肿瘤微环境，这将导致转移性癌症的新治疗策略。