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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：
Ann Marie Pendergast
金额：
$ 46.45万
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/10581652
关键词：
Address Adenocarcinoma Cell Animal Model Astrocytes Brain Brain Neoplasms Cancer Etiology Cancer Patient Cell Communication 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 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 biomarker identification blood-brain barrier crossing 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 single nucleus RNA-sequencing therapeutic target transcription factor transcriptomics treatment response tumor tumor microenvironment tumor progression

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