Development of microfluidic blood-brain tumor barrier model to screen chemotherapeutic strategies for breast cancer brain metastases

项目摘要 脑转移，即源自其他器官的脑内癌症的远处复发，发生在30%的乳腺癌中。 是癌症患者的主要死因之一。这是理解的主要障碍， 治疗脑转移瘤是脑血管周围微环境的复杂性， 在转移进展、化疗药物的递送和功效中的关键作用，以及化疗药物的副作用。 化疗此外，乳腺癌显示出不同的治疗反应和疾病进展 因此，对治疗方案的临床分析和评价需要 具有长期临床病史的患者的较大随机化样本。然而，动物模型， 用于筛选癌症治疗策略的常用平台，对于癌症治疗策略的有效性具有固有的限制。 测试大量可能的药物组合，搁置争议的程度， 与人类疾病的临床相关性。在这个项目中，我们的目标是开发一个可靠的，临床相关的体外 乳腺癌脑转移实验模型的建立及化疗药物的筛选。更 具体来说，我们将在水凝胶中重建脑血管周围的复杂微环境， 包含微流控芯片，完成其3D细胞网络和周围的血流模拟 微流体技术。这种人造但类似天然的脑血管的临床意义 环境将通过乳腺癌细胞的行为来确认，这些行为与临床数据相似， 对抗癌药物的反应。我们的乳腺癌脑转移模型将是一个时间和成本效益的测试 用于筛选和确定每个患者的最佳治疗选择以及预测和 预防个体患者脑转移发展的风险。非常有前途的，新 从该项目中确定的化疗靶点将导致临床前研究，在这些研究中，我们的模型可以 进一步发挥实验平台的作用。此外，通过将个体患者的细胞整合到 我们的体外系统，我们最终将能够建立患者特异性模型，开辟一个真正的可能性， 为每位患者提供个性化治疗。

Project Summary Brain metastasis, the distant relapse of a cancer in brain originally from another organ, occurs in 30% of breast cancer patients and is one of the leading causes of their mortality rate. A major barrier for understanding and treating brain metastasis is the complexity of the microenvironment around the brain blood vessel which plays critical roles in metastatic progression, delivery and efficacy of chemotherapeutic drugs, and the side effects of chemotherapy. In addition, breast cancer shows distinct therapeutic responses and disease progression across individual patients and thus the clinical analysis and evaluation of the treatment options require much larger randomized samples of patients with long-term clinical history. However, animal models, the most commonly used platform for screening cancer treatment strategies, have the inherent limitation in efficiency for testing the vast number of possible drug combinations, setting aside the controversy on the degree of their clinical relevance to the human diseases. In this project, we aim to develop a reliable, clinically relevant in vitro experimental model of breast cancer brain metastasis for efficient screening of chemotherapy drugs. More specifically, we will reconstruct the complex microenvironment around the brain blood vessel within a hydrogel- containing microfluidic chip, complete with its 3D cellular network and the surrounding bloodstream simulated with microfluidics technology. The clinical relevance of this artificial yet native-like brain blood vessel environment will be confirmed through the breast cancer cells behaviors akin to the clinical data in terms of the response to anti-cancer agents. Our breast cancer brain metastasis model will be a time- and cost-efficient test bed for screening and identifying the optimal treatment choice for each patient as well as for predicting and preventing the risk of brain metastasis development in individual patients. The highly promising, new chemotherapeutic targets identified from this project will lead to preclinical studies in which our model can further serve as an effective experimental platform. Furthermore, by incorporating individual patients’ cells into our in vitro system, we will eventually be able to build patient-specific models, opening up a possibility of truly customized treatment for each patient.