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：
10366021
负责人：
Ann Marie Pendergast
金额：
$ 47.98万
依托单位：
DUKE UNIVERSITY
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

来源：
https://reporter.nih.gov/project-details/10366021
关键词：
Address Adenocarcinoma Cell Animal Model Astrocytes Biological Markers Blood - brain barrier anatomy Brain Brain Neoplasms Cancer Etiology Cancer Patient Cell Communication Cell Nucleus Cells Cessation of life Clinical Trials Data Diagnosis Differentiated Gene Disease Drug usage Exhibits Genes Genetic Genetic Transcription Growth High Prevalence Human Impaired cognition Impairment Inflammatory Response Knowledge Link Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic malignant neoplasm to brain Microglia Molecular Morbidity - disease rate Neoplasm Metastasis Nervous system structure Neurodegenerative Disorders Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neurologic Symptoms Neuronal Differentiation Neurons Neurosciences Pathogenesis Pathway interactions Patients Phosphotransferases Process Protein Tyrosine Kinase Quality of life Reporting Research Research Personnel Role Scientist Seizures Signal Transduction Survival Rate Technology Testing Time Transcript Transcription Coactivator Tropism brain dysfunction brain parenchyma cancer type cell type druggable target effective therapy experience experimental study inhibitor innovation leukemia lung cancer cell mimicry mortality mouse model neoplastic cell neurotoxic neurotoxicity novel novel marker pre-clinical response therapeutic target transcription factor transcriptome sequencing transcriptomics treatment response tumor tumor microenvironment tumor progression

Address Adenocarcinoma Cell Animal Model Astrocytes Biological Markers Blood - brain barrier anatomy Brain Brain Neoplasms Cancer Etiology Cancer Patient Cell Communication Cell Nucleus Cells Cessation of life Clinical Trials Data Diagnosis Differentiated Gene Disease Drug usage Exhibits Genes Genetic Genetic Transcription Growth High Prevalence Human Impaired cognition Impairment Inflammatory Response Knowledge Link Lung Adenocarcinoma Lung Neoplasms Malignant Neoplasms Malignant neoplasm of lung Mediating Metastatic malignant neoplasm to brain Microglia Molecular Morbidity - disease rate Neoplasm Metastasis Nervous system structure Neurodegenerative Disorders Neuroepithelial, Perineurial, and Schwann Cell Neoplasm Neurologic Symptoms Neuronal Differentiation Neurons Neurosciences Pathogenesis Pathway interactions Patients Phosphotransferases Process Protein Tyrosine Kinase Quality of life Reporting Research Research Personnel Role Scientist Seizures Signal Transduction Survival Rate Technology Testing Time Transcript Transcription Coactivator Tropism brain dysfunction brain parenchyma cancer type cell type druggable target effective therapy experience experimental study inhibitor innovation leukemia lung cancer cell mimicry mortality mouse model neoplastic cell neurotoxic neurotoxicity novel novel marker pre-clinical response therapeutic target transcription factor transcriptome sequencing transcriptomics treatment response tumor tumor microenvironment tumor progression

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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.

脑转移解释了生存下降，发病率增加，认知受损和生活质量差对于肺癌患者。缺乏有效治疗脑转移治疗的疗法对调节脑实质定植的分子机制的了解有限。肺癌是美国癌症死亡率的主要原因，总五年生存率约为16％。估计每年〜234,030例新病例和约154,050例肺癌死亡。值得注意的是，约有40％的肺癌患者在诊断时有转移酶，并且脑转移的患病率最高（40-60％）在所有癌症类型中。当前治疗肺癌脑转移酶的疗法已被证明是由于可变，瞬态和不完整的响应。我们最近报道了ABL激酶的变构抑制剂越过血脑屏障（BBB），并显着损害了脑转移的生长。增强的表达 ABL和下游靶基因与肺腺癌患者的存活缩短有关。我们有确定了介导肺癌脑转移潜力的特定ABL调节的转录因子通过在脑转移和神经细胞之间恢复相互串扰来恢复细胞。意外的角色 ABL调节的转录网络是它促进了脑转移性神经元特征的表达肺癌细胞。通过肺肿瘤获取“神经元模仿”是一种潜在的机械适应通过选择神经元细胞的功能，星形胶质细胞的功能，实现大脑中的有效定殖和产物和小胶质细胞。在这方面，我们发现抑制肺癌细胞中ABL激酶会损害有害脑小胶质细胞的炎症反应。总体假设是ABL调节的转录网络促进脑转移，并且抑制ABL信号传导可通过破坏脑肿瘤微环境中脑转移细胞和居民神经元细胞之间的串扰。为了评估这一假设，我们提出了三个具体目标：1）定义ABL调节的转录网络促进肺癌脑转移以及ABL激酶失活的机制脑转移。 2）评估ABL激酶的失活是否会损害大脑的转移性定植实质通过破坏肿瘤神经细胞串扰，同时伴随着肿瘤诱导的神经毒性。 3）定义肺癌脑转移的转录景观，并评估是否对ABL调节转录组特征确定向大脑转移的肺癌类型。为此，我们将雇用不仅在脑转移中，而且还包括周围脑实质的神经细胞类型。这些实验的结果将显示肺癌脑转移的转录景观，对于识别生物标志物和可起诉的至关重要目标。生成的数据将标识新的信号网络，以促进脑转移并发现新颖治疗该疾病并降低肿瘤诱导的神经毒性的靶标。