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:
  • 金额:
    $ 74.93万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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Don X Nguyen其他文献

Don X Nguyen的其他文献

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{{ truncateString('Don X Nguyen', 18)}}的其他基金

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。
  • 批准号:
    9920134
  • 财政年份:
    2019
  • 资助金额:
    $ 74.93万
  • 项目类别:
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。
  • 批准号:
    10616672
  • 财政年份:
    2019
  • 资助金额:
    $ 74.93万
  • 项目类别:
Project 3: Identifying and targeting mediators of CNS metastasis from lung cancer
项目3:识别和靶向肺癌中枢神经系统转移的介质
  • 批准号:
    10203856
  • 财政年份:
    2015
  • 资助金额:
    $ 74.93万
  • 项目类别:
A novel lineage pathway controls metabolic adaptation by metastatic lung cancers
一种新的谱系途径控制转移性肺癌的代谢适应
  • 批准号:
    8984877
  • 财政年份:
    2014
  • 资助金额:
    $ 74.93万
  • 项目类别:
A novel lineage pathway controls metabolic adaptation by metastatic lung cancers
一种新的谱系途径控制转移性肺癌的代谢适应
  • 批准号:
    9182876
  • 财政年份:
    2014
  • 资助金额:
    $ 74.93万
  • 项目类别:
Epigenetic modulation of lung cancer metastasis by a novel long intergenic RNA
新型长基因间RNA对肺癌转移的表观遗传调节
  • 批准号:
    8900254
  • 财政年份:
    2014
  • 资助金额:
    $ 74.93万
  • 项目类别:
A Novel Lineage Specific Metastasis Suppressor Pathway in Lung Cancer
肺癌中一种新的谱系特异性转移抑制途径
  • 批准号:
    8681391
  • 财政年份:
    2012
  • 资助金额:
    $ 74.93万
  • 项目类别:
A NOVEL LINEAGE SPECIFIC METASTASIS PATHWAY IN LUNG CANCER
肺癌中一种新的谱系特异性转移途径
  • 批准号:
    10066312
  • 财政年份:
    2012
  • 资助金额:
    $ 74.93万
  • 项目类别:
A NOVEL LINEAGE SPECIFIC METASTASIS PATHWAY IN LUNG CANCER
肺癌中一种新的谱系特异性转移途径
  • 批准号:
    9884455
  • 财政年份:
    2012
  • 资助金额:
    $ 74.93万
  • 项目类别:
A Novel Lineage Specific Metastasis Suppressor Pathway in Lung Cancer
肺癌中一种新的谱系特异性转移抑制途径
  • 批准号:
    8436668
  • 财政年份:
    2012
  • 资助金额:
    $ 74.93万
  • 项目类别:

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