Deconvolution and interruption of the cancer-neuro-immune axis facilitating brain metastases

1摘要-总体组件 2 3脑转移的发展，高达40%的癌症患者经历，标志着一个明确的转折 生存率和生活质量4分。脑肿瘤组织的不可及性阻碍了我们的进展， 5了解和治疗脑转移瘤，并定期将患者排除在临床试验之外。的 6斯坦福大学脑转移联盟将脑和癌症专家团结在一起，共同致力于改善我们的脑转移。 7脑转移瘤的理解和治疗，这是一种目前日益增加但服务不足的癌症子集 8例患者。为了实现上述目标，我们：（1）设计了一个组织结构， 9科学家在我们的综合工作;（2）开发高度创新和互补的项目，以了解 10并破坏支持脑转移的癌症-神经免疫轴;和（3）创建神经病理学 11和ToolKit Cores，使参与者可以随时访问人类标本和尖端技术 12科学家我们希望能够识别和靶向脑转移的关键介质， 13个病人 [14]关于将肿瘤细胞驱动到大脑并使其在大脑中生长的独特机制知之甚少。 15独特的微环境，部分由正常脑细胞支持。简化了对人脑的访问 16个标本，结合肿瘤微环境建模和操作的创新， 17个基本进步的合作机会。我们的专家，高效的合作者组成的综合团队 18旨在了解肿瘤细胞（项目1），常驻小胶质细胞（项目2）和肿瘤细胞（项目2）的内在特征。 19全身免疫系统（项目3）有助于脑转移的发生和进展。这些项目 20通过集中访问人类患者脑转移瘤样品（NeuroPathology Core）来促进，和 21种新颖的多重分析和疾病建模（ToolKit Core）。我们的多学科医生顾问 22 Network提供临床见解，并帮助我们将研究结果快速转化为患者的临床试验 23例脑转移。行政和数据管理核心将提供业务支助 第24章成功实现计划目标我们的患者倡导者帮助整合和 25将我们的工作传达给更大的科学和患者社区。 26.我们已经成立了少数几个具有专门知识、兴趣和能力的小组，以解决根本的问题。 27脑转移瘤的机制和治疗机会。只有通过这种联合的协同作用， 28、这个项目是可行的。这些创新方法将确保我们的研究结果反映并可翻译为 29人类疾病，使我们的多学科团队能够为诊断和治疗奠定基础 30进步

1 ABSTRACT – OVERALL COMPONENT 2 3 The development of brain metastases, experienced by up to 40% of cancer patients, marks a clear inflection 4 point in survival and quality of life. The inaccessibility of brain tumor tissue has stymied progress in our 5 understanding and treatment of brain metastases, and patients are regularly excluded from clinical trials. The 6 Stanford Brain Metastasis Consortium has unified brain and cancer experts in the singular goal of improving our 7 understanding and treatment of brain metastases, a currently increasing yet underserved subset of cancer 8 patients. To accomplish the above goal, we have: (1) designed an organizational structure that supports 9 scientists in our integrated work; (2) developed highly innovative and complementary Projects to understand 10 and disrupt the cancer-neuro-immune axis supporting brain metastases; and (3) created NeuroPathology 11 and ToolKit Cores to make human specimens and cutting-edge technologies readily accessible to participating 12 scientists. We expect to identify and target key mediators of brain metastasis, with therapeutic benefit for 13 patients. 14 Little is known about the distinct mechanisms that drive tumor cells to the brain and allow them to grow in this 15 unique microenvironment, supported in part by normal brain cells. Streamlined access to human brain 16 specimens, combined with innovations in modeling and manipulation of the tumor microenvironment, create this 17 collaborative opportunity for fundamental advancement. Our expert, integrated team of productive collaborators 18 aims to understand how the intrinsic features of tumor cells (Project 1), resident microglia (Project 2), and the 19 systemic immune system (Project 3) contribute to the onset and progression of brain metastases. These projects 20 are facilitated by centralized access to human patient brain metastases samples (NeuroPathology Core), and 21 novel, multiplexed analyses and disease modeling (ToolKit Core). Our multidisciplinary physician Consultant 22 Network provides clinical insight and helps in the rapid translation of our findings into clinical trials for patients 23 with brain metastases. The Administrative and Data Management Core will provide the operational support 24 necessary to successfully achieve the goals of the program. Our Patient Advocates help to integrate and 25 communicate our work to the greater scientific and patient communities. 26 We have formed one of the few groups with the expertise, interest, and capacity to address the underlying 27 mechanisms of and therapeutic opportunities for brain metastases. Only through this combined synergy would 28 this project be possible. These innovative methods will ensure our findings are reflective of and translatable to 29 the human disease, enabling our multidisciplinary team to lay the foundation for diagnostic and therapeutic 30 advancements.