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: 10165993
• 负责人: Jacob Peter Hoj
• 金额: $ 8.15万
• 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 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10165993
• 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; Treatment Efficacy; Tumor Burden; Tumor Cell Invasion; Tumor Subtype; Up-Regulation; Work; autocrine; cancer cell; 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/antagonist; loss of function; melanoma; mortality; mouse model; mutant; neoplastic cell; novel; novel strategies; proteotoxicity; response; success; targeted agent; targeted treatment; 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.

摘要 尽管出现了用于治疗各种固体的靶向治疗和免疫检查点抑制剂 肿瘤类型，肿瘤细胞向远处器官部位的转移扩散仍然是 癌症相关死亡率。由于改善了对原发肿瘤负担的管理，患者的存活率增加， 尤其令人担忧的是，脑转移瘤的发病率不断上升，几乎没有例外地降低了患者的存活率。 几周或几个月的数量级。脑转移最常见于卵巢癌患者。 肺癌、乳房和黑色素瘤。针对“驱动因素”突变和基因扩增的治疗，如EGFR (肺)、HER2(乳房)和RAF/MEK(黑色素瘤)在治疗脑转移瘤方面无效，因为 短暂的反应和缺乏血脑屏障的通透性。检查点抑制剂的使用 脑转移瘤的治疗也取得了有限的临床成功。在目前的情况下，没有有效的 脑转移患者的治疗方法已经存在，因此发现了新的策略，通过这种策略 治疗脑内转移性疾病是临床的迫切需要。这份建议书描述了我们正在进行的工作 研究脑转移性肺癌细胞中新的Ax1-ABL2-TAZ信号轴 脑转移瘤小鼠体内模型的建立及后续机制研究。我们 发现这个信号轴的激活驱动了脑转移相关基因的表达，从而使 播散性肿瘤细胞在脑微环境中适应和存活。重要的是，有针对性地抑制 AXL或ABL激酶损害脑转移瘤的生长，并显著延长脑转移瘤的生存期。 生老鼠。最后，我以博士后候选人的身份描述了未来的研究，结合我的 目前在细胞信号和高通量功能基因组学体内小鼠模型的使用方面的专业知识 无偏见地确定控制实体肿瘤向大脑转移的分子介质的平台。