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
• 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
• 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

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。缺乏治疗脑转移瘤的有效疗法，部分原因是 对调节脑实质定植的分子机制了解有限。肺癌 是美国癌症死亡的主要原因，总体五年生存率约为 16%。估计 每年约有 234,030 例新发肺癌病例和约 154,050 例肺癌死亡病例。值得注意的是，约 40% 的肺癌患者 诊断时已发生转移，且脑转移发生率最高 (40-60%) 在所有癌症类型中。目前治疗肺癌脑转移的疗法已被证明无效，原因是 可变的、瞬态的和不完整的响应。我们最近报道了 ABL 激酶的变构抑制剂 穿过血脑屏障（BBB）并显着损害脑转移瘤的生长。增强表达 ABL 和下游靶基因的缺失与肺腺癌患者的生存期缩短有关。我们有 鉴定出介导肺癌脑转移潜能的特定 ABL 调节转录因子 通过调节脑转移瘤和神经细胞之间的相互串扰来调节细胞。这个角色意想不到 ABL 调节的转录网络促进脑转移中神经元特征的表达 肺癌细胞。肺部肿瘤获得“神经元拟态”是一种潜在的机制适应 通过选择神经元细胞、星形胶质细胞的功能，在大脑中实现有效的定植和生长 和小胶质细胞。在这方面，我们发现抑制肺癌细胞中的 ABL 激酶会损害有害细胞。 脑小胶质细胞的炎症反应。总体假设是 ABL 调控的转录 网络促进脑转移，抑制 ABL 信号传导可通过以下方式增强肿瘤细胞的脆弱性： 破坏脑肿瘤微环境中脑转移细胞和常驻神经细胞之间的串扰。 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 激酶失活损害的机制 脑转移。 2) 评估 ABL 激酶失活是否会损害大脑的转移定植 通过破坏肿瘤-神经细胞串扰来破坏实质，同时减弱肿瘤诱导的神经毒性。 3）定义肺癌脑转移的转录格局并评估ABL是否调控 转录组特征可识别转移至大脑的肺癌类型。为此，我们将聘请 最先进的转录组技术不仅可以评估脑转移中的转录变化，还可以评估转录变化 也存在于周围脑实质的神经细胞类型中。这些实验的结果将揭示 肺癌脑转移的转录景观，对于识别生物标志物和可操作至关重要 目标。生成的数据将识别促进脑转移的新信号网络并发现新的信号网络 目标是治疗这种疾病并减少肿瘤引起的神经毒性。