Uncovering actionable signaling pathways required for solid tumor brain metastasis

摘要 尽管出现了靶向治疗和免疫检查点抑制剂，用于治疗各种实体瘤， 肿瘤类型，肿瘤细胞向远处器官部位的转移性扩散仍然是肿瘤发生的主要决定因素。 癌症相关死亡率。由于原发性肿瘤负荷管理的改善， 特别值得关注的是脑转移的发病率不断上升， 几周或几个月的数量级。转移到脑中最常见于患有肿瘤的患者， 肺乳腺和黑色素瘤靶向“驱动”突变和基因扩增（如EGFR）的治疗 HER 2（肺）、HER 2（乳腺）和RAF/MEK（黑色素瘤）在治疗脑转移方面一直是无效的， 短暂反应和缺乏血脑屏障屏障通透性。检查点抑制剂用于 脑转移瘤的管理也遇到了有限的临床成功。就目前而言，没有有效的 对于患有脑转移的患者存在治疗，因此发现了新的策略， 治疗脑内的转移性疾病是迫切的临床需要。本提案描述了我们正在进行的工作 通过以下方法表征脑转移性肺癌细胞中新的AXL-ABL 2-TAZ信号传导轴： 脑转移瘤体内小鼠模型的实施与后续机制研究相结合。我们 发现这个信号轴的激活驱动脑转移相关基因的表达， 扩散的肿瘤细胞在脑微环境中适应和生存。重要的是，靶向抑制 AXL或ABL激酶损害脑转移瘤的生长，并显着延长脑转移瘤的生存期- 产鼠最后，我描述了未来的研究将作为一个博士后候选人进行结合我的 目前在细胞信号传导和使用体内小鼠模型与高通量功能基因组学方面的专业知识 平台，以无偏见地确定控制实体瘤转移到大脑的分子介质。

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.