Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis

靶向肿瘤-神经细胞相互作用抑制肺癌脑转移

基本信息

  • 批准号:
    10581652
  • 负责人:
  • 金额:
    $ 46.45万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2021
  • 资助国家:
    美国
  • 起止时间:
    2021-03-05 至 2026-02-28
  • 项目状态:
    未结题

项目摘要

Brain metastases account for decreased survival, increased morbidity, impaired cognition and poor quality of life for patients with lung cancer. Effective therapies for the treatment of brain metastases are lacking due in part to limited knowledge of the molecular mechanisms that regulate colonization of the brain parenchyma. Lung cancer is the leading cause of cancer mortality in the U.S., with an overall five-year survival rate of ~16%. It is estimated that ~ 234,030 new cases and ~ 154,050 deaths of lung cancer per year. Notably, ~40% of lung cancer patients have metastases at the time of diagnosis, and exhibit the highest prevalence of brain metastasis (40-60 %) among all cancer types. Current therapies to treat lung cancer brain metastases have proven ineffective due to variable, transient and incomplete responses. We recently reported that allosteric inhibitors of the ABL kinases cross the blood-brain barrier (BBB) and markedly impair the growth of brain metastases. Enhanced expression of ABL and downstream target genes is linked to shortened survival of lung adenocarcinoma patients. We have identified specific ABL-regulated transcription factors that mediate the brain metastatic potential of lung cancer cells by regulating reciprocal crosstalk between brain metastases and neural cells. An unexpected role of this ABL-regulated transcription network is that it promotes expression of neuronal signatures in brain metastatic lung cancer cells. Acquisition of “neuronal mimicry” by lung tumors is a potential mechanistic adaptation to achieve effective colonization and outgrowth in the brain by co-opting the function of neuronal cells, astrocytes and microglia. In this regard, we found that inhibition of ABL kinases in lung cancer cells impairs deleterious inflammatory responses of brain microglia cells. The overall hypothesis is that ABL-regulated transcription networks promote brain metastasis, and that inhibition of ABL signaling enhances tumor cell vulnerabilities by disrupting crosstalk between brain metastatic cells and resident neural cells in the brain tumor microenvironment. To evaluate this hypothesis, we propose three specific aims: 1) Define the ABL-regulated transcription networks that promote lung cancer brain metastasis and the mechanisms whereby inactivation of ABL kinases impairs brain metastasis. 2) Evaluate whether inactivation of ABL kinases impairs metastatic colonization of the brain parenchyma by disrupting tumor-neural cell crosstalk, while concomitantly blunting tumor-induced neurotoxicity. 3) Define the transcriptional landscape of lung cancer brain metastases and assess whether ABL-regulated transcriptomic signatures identify lung cancer types that metastasize to the brain. To this end we will employ state-of-the-art transcriptomic technologies to evaluate transcriptional changes, not only in brain metastasis, but also among neural cell types in the surrounding brain parenchyma. Results from these experiments will reveal the transcriptional landscapes of lung cancer brain metastases, critical to identify biomarkers and actionable targets. Data generated will identity novel signaling networks that promote brain metastases and uncover novel targets to treat this disease and decrease tumor-induced neurotoxicity.
脑转移导致生存率降低、发病率增加、认知功能受损和生活质量下降

项目成果

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Ann Marie Pendergast其他文献

Ann Marie Pendergast的其他文献

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{{ truncateString('Ann Marie Pendergast', 18)}}的其他基金

Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis
靶向肿瘤-神经细胞相互作用抑制肺癌脑转移
  • 批准号:
    10164550
  • 财政年份:
    2021
  • 资助金额:
    $ 46.45万
  • 项目类别:
Targeting tumor-neural cell interactions to inhibit lung cancer brain metastasis
靶向肿瘤-神经细胞相互作用抑制肺癌脑转移
  • 批准号:
    10366021
  • 财政年份:
    2021
  • 资助金额:
    $ 46.45万
  • 项目类别:
Targeting ABL kinases to regulate epithelial cell plasticity and regeneration following injury
靶向 ABL 激酶调节损伤后上皮细胞可塑性和再生
  • 批准号:
    10666351
  • 财政年份:
    2020
  • 资助金额:
    $ 46.45万
  • 项目类别:
Targeting ABL kinases to regulate epithelial cell plasticity and regeneration following injury
靶向 ABL 激酶调节损伤后上皮细胞可塑性和再生
  • 批准号:
    10396637
  • 财政年份:
    2020
  • 资助金额:
    $ 46.45万
  • 项目类别:
Novel target for therapy refractory lung tumors
治疗难治性肺部肿瘤的新靶点
  • 批准号:
    9269186
  • 财政年份:
    2015
  • 资助金额:
    $ 46.45万
  • 项目类别:
Novel target for therapy refractory lung tumors
治疗难治性肺部肿瘤的新靶点
  • 批准号:
    9065535
  • 财政年份:
    2015
  • 资助金额:
    $ 46.45万
  • 项目类别:
Novel target for therapy refractory lung tumors
治疗难治性肺部肿瘤的新靶点
  • 批准号:
    8882940
  • 财政年份:
    2015
  • 资助金额:
    $ 46.45万
  • 项目类别:
Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis
癌症侵袭和转移中多种细胞表面受体的激酶靶点
  • 批准号:
    8657899
  • 财政年份:
    2011
  • 资助金额:
    $ 46.45万
  • 项目类别:
Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis
癌症侵袭和转移中多种细胞表面受体的激酶靶点
  • 批准号:
    8458615
  • 财政年份:
    2011
  • 资助金额:
    $ 46.45万
  • 项目类别:
Kinase Target of Diverse Cell Surface Receptors in Cancer Invasion and Metastasis
癌症侵袭和转移中多种细胞表面受体的激酶靶点
  • 批准号:
    8199099
  • 财政年份:
    2011
  • 资助金额:
    $ 46.45万
  • 项目类别:

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