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

• 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
• 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

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 尽管出现了用于治疗多种实体瘤的靶向疗法和免疫检查点抑制剂 肿瘤类型中，肿瘤细胞向远处器官部位的转移扩散仍然是主要决定因素 癌症相关死亡率。由于原发性肿瘤负荷管理的改善，患者的生存率有所提高， 特别值得关注的是脑转移发病率的上升，几乎没有例外，这会降低患者的生存率 大约几周或几个月。脑转移最常见于患有脑肿瘤的患者 肺癌、乳腺癌和黑色素瘤。针对“驱动”突变和基因扩增（例如 EGFR）的疗法 （肺）、HER2（乳腺癌）和 RAF/MEK（黑色素瘤）在治疗脑转移方面无效，原因是 短暂反应和缺乏血脑屏障渗透性。使用检查点抑制剂 脑转移的治疗也取得了有限的临床成功。从目前情况看，没有有效的 针对患有脑转移的患者存在治疗方法，因此发现了新的策略 治疗脑内转移性疾病是临床的迫切需要。该提案描述了我们正在进行的工作 通过以下方式表征脑转移性肺癌细胞中的新型 AXL-ABL2-TAZ 信号轴 建立体内脑转移小鼠模型并结合后续机制研究。我们 发现该信号轴的激活驱动脑转移相关基因的表达，从而允许 播散的肿瘤细胞适应并在大脑微环境中生存。重要的是，有针对性的抑制 AXL 或 ABL 激酶会损害脑转移瘤的生长并显着延长脑转移瘤的生存期 承载老鼠。最后，我结合我的经验描述了作为博士后候选人未来要进行的研究 目前在细胞信号传导方面的专业知识以及使用具有高通量功能基因组学的体内小鼠模型 公正地识别控制实体瘤脑转移的分子介质的平台。