Uncovering actionable signaling pathways required for solid tumor brain metastasis

发现实体瘤脑转移所需的可行信号通路

基本信息

批准号：
10401924
负责人：
Jacob Peter Hoj
金额：
$ 8.9万
依托单位：
DUKE UNIVERSITY
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：
2019-09-09 至 2022-10-21
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401924
关键词：
ABL2 gene Automobile Driving Biological Blood - brain barrier anatomy Brain Breast Breast Carcinoma Breast Melanoma CRISPR screen Cell Line Cell Survival Clinic Clinical Clinical Trials Complication Coupled Data Data Set Dependence Disease Distant Doctor of Philosophy Drug Targeting ERBB2 gene Environment Epidermal Growth Factor Receptor FDA approved Family Feedback Follow-Up Studies Foundations Future Gene Amplification Gene Expression Gene Expression Profiling Gene Targeting Genes Genetic Transcription Genomic approach Goals Human Cell Line Immune checkpoint inhibitor Impairment In Vitro Incidence KRAS2 gene Lung Lung Adenocarcinoma Lung Neoplasms MEKs Malignant Neoplasms Malignant neoplasm of lung Mammary Neoplasms Mediating Mediator of activation protein Metastatic malignant neoplasm to brain Modeling Molecular Mus Neoplasm Metastasis Neural Cell Adhesion Molecule L1 Organ Paper Pathway interactions Patient-Focused Outcomes Patients Penetrance Pharmaceutical Preparations Pharmacology Phenotype Phosphotransferases Primary Neoplasm Principal Investigator Proto-Oncogene Proteins c-abl Research Research Project Grants Role Signal Pathway Signal Transduction Site Solid Neoplasm Stress Technology Therapeutic Time Training Transcription Coactivator Transducers Tumor Burden Tumor Cell Invasion Tumor Subtype Up-Regulation Work autocrine brain dysfunction career comparative driver mutation effective therapy follow-up functional genomics gene product genome-wide genomic platform heat-shock factor 1 high-throughput drug screening improved in vivo in vivo Model inhibitor loss of function lung cancer cell melanoma mortality mouse model mutant neoplastic cell novel novel strategies proteotoxicity response success targeted agent targeted treatment therapeutically effective triple-negative invasive breast carcinoma tumor

项目摘要

ABSTRACT Despite the emergence of targeted therapies and immune checkpoint inhibitors for the treatment of diverse solid tumor types, the metastatic spread of tumor cells to distant organ sites remains the primary determinant of cancer-related mortality. As patient survival increases owing to improved management of primary tumor burden, of particular concern is the rising incidence of brain metastases which with few exceptions reduce patient survival to the order of weeks or months. Metastases to the brain are most commonly seen in patients with tumors of the lung, breast, and melanoma. Therapies targeting “driver” mutations and gene amplifications such as EGFR (lung), HER2 (breast), and RAF/MEK (melanoma) have been ineffective at treating brain metastases owing to transient responses and lack of blood-brain barrier penetrance. The use of checkpoint inhibitors for the management of brain metastases has also been met with limited clinical success. As it stands, no effective therapies exist for patients suffering from brain metastases, therefore the discovery of novel strategies by which to treat metastatic disease within the brain is an urgent clinical need. This proposal describes our ongoing work to characterize a novel AXL-ABL2-TAZ signaling axis in brain-metastatic lung cancer cells through the implementation of in vivo mouse models of brain metastasis combined with follow-up mechanistic studies. We find that activation of this signaling axis drives expression of brain metastasis-associated genes which allow disseminated tumor cells to adapt and survive in the brain microenvironment. Importantly, targeted inhibition of AXL or the ABL kinases impairs brain-metastatic outgrowth and significantly extends survival in brain metastasis- bearing mice. Lastly, I describe future studies to be conducted as a postdoctoral candidate by combining my current expertise in cell signaling and the use of in vivo mouse models with high-throughput functional genomics platforms to unbiasedly identify the molecular mediators governing solid tumor metastasis to the brain.

抽象的尽管出现了有针对性的疗法和免疫粘液抑制剂，以治疗多样的固体肿瘤类型，肿瘤细胞向遥远器官部位的转移扩散仍然是主要的确定器与癌症有关的死亡率。随着患者生存的增加，由于对原发性肿瘤燃烧的治疗有所提高，特别关注的是脑转移事件的不断增长，除少数例外，降低了患者的生存到几周或几个月的订单。向大脑转移最常见于患有肿瘤的患者肺，乳房和黑色素瘤。靶向“驱动器”突变和基因扩增的疗法，例如EGFR （肺），HER2（乳房）和RAF/MEK（黑色素瘤）在治疗脑转移方面无效短暂反应和缺乏血脑屏障的渗透性。使用检查点抑制剂对脑转移的管理也有限，临床成功有限。就目前而言，无效为患有脑转移的患者存在疗法，因此发现了新型策略在大脑内治疗转移性疾病是紧迫的临床需求。该建议描述了我们正在进行的工作表征新的AXL-ABL2-TAZ信号轴，通过脑部转移性肺癌细胞实施脑转移的体内小鼠模型与后续机械研究相结合。我们发现该信号轴的激活驱动与脑转移相关基因的表达，这允许传播肿瘤细胞以适应和生存在脑微环境中。重要的是，有针对性的抑制 AXL或ABL激酶会损害脑部转移的产物，并显着延长脑转移的生存率轴承老鼠。最后，我将未来的研究描述为通过结合我的博士后候选人当前在细胞信号传导和具有高通量功能基因组的体内小鼠模型的专业知识平台可公开识别管理大脑实体瘤转移的分子介质。