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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：
10376749
负责人：
Don X Nguyen
金额：
$ 74.93万
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/10376749
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 Regimen Relapse Research Resistance Resources Role Sampling Series Signal Pathway Site Source Specimen Testing Tissues Tyrosine Kinase Inhibitor base insight interdisciplinary approach lung cancer cell molecular targeted therapies mutant neoplastic cell novel novel therapeutic intervention novel therapeutics patient derived xenograft model patient subsets prevent programs refractory cancer 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.

项目总结