Recapitulating Ductal Carcinoma on a Chip for Personalized Breast Cancer Therapy

 描述（由申请人提供）：癌症是全世界的主要死亡原因之一，2015年估计死亡率接近1000万，其中仅在美国预计将发生总计1，658，370例新发癌症病例和589，430例癌症死亡。特别是，乳腺癌是美国人中流行的癌症之一：美国约1/8（12%）的女性可能在其一生中发展为浸润性乳腺癌。2015年，估计美国女性将诊断出231，480例浸润性乳腺癌（80%浸润性导管癌[IDC]）和60，290例原位癌（>85%导管原位癌[DCIS]）的新病例，导致约40，290例死亡。虽然乳腺癌生存率已取得了巨大的改善，目前的药物管理程序依赖于化疗，然后进行放射学扫描往往会导致差异的癌症护理，这在很大程度上是由肿瘤内异质性引起的药物反应的差异。例如，当一种可能有效的药物被施用时，在药物无效和疾病进展被发现之前，它需要长时间的随访。然后，患者将接受替代药物进行治疗，导致i）对健康器官的累积全身毒性; ii）对可能进一步进展的癌症的时间响应性受损，使得治疗更加困难;以及iii）治疗计划的高成本。该提案的目标是通过工程化和验证多组分导管癌芯片平台来解决上述挑战，该平台通过i）构建3D血管化基质包埋可灌注、互连的微血管; ii）通过生物打印引入基底膜涂覆的导管样结构; iii）构建血管化基质包埋可灌注、互连的微血管; iv）构建血管化基质包埋可灌注、互连的微血管; iv）构建血管化基质包埋可灌注、互连的微血管; iv）构建血管化基质包埋可灌注、互连的微血管。iii）在芯片上诱导导管癌的进展、侵袭和血管生成，所述芯片在体内再现这些过程; iv）建立用于抗癌药物筛选的传感器集成平台;以及v）扩展到用于全身药物作用的概念验证研究的肿瘤和多器官芯片平台。将在“动物（小鼠）患者”中验证该平台的有效性。 这一创新平台有望在未来通过应用患者来源的细胞构建个性化芯片方面实现临床变革。

 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.