Recapitulating Ductal Carcinoma on a Chip for Personalized Breast Cancer Therapy

 描述(申请人提供)：癌症是世界上主要的死亡原因之一，2015年估计死亡人数接近1000万，其中仅美国就预计将有1658,370例新癌症病例和589,430例癌症死亡。特别是，乳腺癌是美国人中最常见的癌症之一：在美国，大约八分之一(12%)的女性可能在一生中患上浸润性乳腺癌。据估计，2015年美国女性新确诊的浸润性乳腺癌病例为231,480例(80%为浸润性导管癌[IDCs])，原位癌为60,290例(85%为导管原位癌[DCIS])，死亡人数约为40,290人。虽然乳腺癌的存活率已经得到了极大的改善，但目前依赖于化疗和放射扫描的给药程序经常导致癌症治疗的差异，这主要是由于肿瘤内异质性引起的药物反应的差异造成的。例如，当使用一种假定有效的药物时，需要进行长时间的随访，才能揭示药物的无效和疾病的进展。然后，患者将接受另一种治疗药物，导致：1)对健康器官累积的全身毒性；2)对可能进一步进展的癌症的时间反应能力受损，使治疗更加困难；以及3)治疗计划的成本高昂。这项建议的目标是通过设计和验证一种多组分的芯片上导管癌平台来应对上述挑战，该平台通过以下方式重述体内肿瘤的生物学和生理学：i)构建3D血管基质，嵌入可灌流的、相互连接的微血管；ii)通过生物打印引入基底膜涂层的管状结构；iii)在概括体内这些过程的芯片上诱导导管癌的进展、侵袭和血管生成；iv)建立用于抗癌药物筛选的传感器集成平台；以及v)扩展到一个肿瘤和多器官芯片平台，用于系统性药物效应的概念验证研究。该平台的疗效将在“动物(鼠)患者”身上得到验证。 这一创新平台有望在未来通过应用患者来源的细胞来构建个性化芯片方面产生临床变革。

 DESCRIPTION (provided by applicant): Cancers are among the leading causes of death around the world with an estimated mortality of close to 10 million in 2015, among which a total of 1,658,370 new cancer cases and 589,430 cancer deaths are projected to occur in the US alone. Particularly, breast cancer is one of the prevailing cancers among the Americans: about 1 in 8 (12%) women in the US is likely to develop invasive breast cancer during their lifetime. In 2015, estimated new cases of invasive breast cancer of 231,480 (80% invasive ductal carcinomas [IDCs]) and carcinoma in situ of 60,290 (>85% ductal carcinoma in situ [DCIS]) will be diagnosed in US women, leading to a death toll of about 40,290. Although tremendous improvements in breast cancer survival have been achieved, current drug administration procedures relying on chemotherapy followed by radiographic scans often lead to disparity in cancer care, which is largely caused by the variance in drug responses arose from intratumor heterogeneity. For example, when a presumably effective drug is administered, it requires lengthy follow-ups before the ineffectiveness of the drug and progression of the disease can be revealed. The patient will then receive an alternative drug for treatment, leading to i) accumulated systemic toxicity towards healthy organs; ii) impaired time responsiveness to the cancer which may have further progressed, rendering treatment more difficult; and iii) high cost of the treatment plan. The goal of this proposal is to tackle the aforementioned challenges by engineering and validating a multi- component ductal-carcinoma-on-a-chip platform, which recapitulates the biology and physiology of the tumor in vivo through i) construction of 3D vascularized stroma embedding perfusable, interconnected microvessels; ii) introduction of basement membrane-coated duct-like structures via bioprinting; iii) induction of progression, invasion, and angiogenesis of ductal carcinoma on the chip that recapitulates such processes in vivo; iv) establishment of a sensor-integrated platform for anti-cancer drug screening; and v) extension to a tumor-and- multi-organ-on-a-chip platform for proof-of-concept investigation of systemic drug effect. The efficacy of this platform will be validated in "animal (mouse) patients". This innovative platform is expected to be clinically transformative in the future in building personalized chips through application of patient-derived cells.