Recapitulating Ductal Carcinoma on a Chip for Personalized Breast Cancer Therapy

在芯片上重现导管癌的个体化乳腺癌治疗

• 批准号: 9109971
• 负责人: Yu Shrike Zhang
• 金额: $ 17.82万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-05-16 至 2018-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9109971
• 关键词: Adverse effects; American; Animals; Antineoplastic Agents; Antitumor Drug Screening Assays; Award; Basement membrane; Biology; Biomimetics; Biopsy; Biosensor; Breast Cancer Model; Breast Cancer Patient; Breast Cancer therapy; Carcinoma in Situ; Cause of Death; Cells; Cessation of life; Classification; Couples; Data; Detection; Diagnosis; Disease Progression; Doxorubicin; Drug Kinetics; Duct (organ) structure; Ductal Carcinoma; Engineering; FDA approved; Future; Goals; Health; Heart; Heart Neoplasms; Hydrogels; In Vitro; Investigation; Lead; Liver; Malignant Epithelial Cell; Malignant Neoplasms; Mammary Duct; Mammary Ductal Carcinoma; Mammary Neoplasms; Mentors; Microfluidic Microchips; Microfluidics; Modeling; Mus; Noninfiltrating Intraductal Carcinoma; Organ; Organoids; Patients; Pharmaceutical Preparations; Pharmacotherapy; Phase; Physiology; Procedures; Process; Property; Research; Scanning; Structure; Testing; Time; Tissues; Tumor Markers; Tumor-Derived; Validation; Woman; angiogenesis; base; bioprinting; breast cancer survival; cancer care; cancer health disparity; chemotherapy; cost; design; ductal breast carcinoma; in vivo; individual patient; induced pluripotent stem cell; infiltrating duct carcinoma; innovation; malignant breast neoplasm; mortality; mouse model; neoplastic cell; novel; personalized screening; prototype; response; sensor; systemic toxicity; treatment planning; tumor; tumor heterogeneity; tumor progression; tumorigenesis

 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.

 描述（申请人提供）：癌症是全球主要死亡原因之一，预计 2015 年死亡人数接近 1,000 万人，其中美国预计将新增癌症病例 1,658,370 例，癌症死亡人数为 589,430 例尤其是乳腺癌是美国人中最常见的癌症之一：大约八分之一（12%）的美国女性可能患有乳腺癌。 2015 年，预计将诊断出 231,480 例新发浸润性乳腺癌（80% 浸润性导管癌 [IDC]）和 60,290 例原位癌（>85% 导管原位癌 [DCIS]）。导致美国女性死亡约 40,290 人，尽管乳腺癌生存率已取得巨大改善，但目前的给药程序仍依赖于化疗。随后的放射线扫描通常会导致癌症护理的差异，这很大程度上是由于肿瘤内异质性引起的药物反应差异造成的，例如，当服用一种看似有效的药物时，在药物无效之前需要长时间的随访。然后，患者将接受替代药物进行治疗，从而导致 i) 对健康器官的累积毒性；ii) 对可能进一步进展的癌症的时间反应性受损，使治疗更加困难；和三）该提案的目标是通过设计和验证多组件导管癌芯片平台来应对挑战，该平台通过 i ) 概括了体内肿瘤的生物学和生理学。构建嵌入可灌注、相互连接的微血管的 3D 血管化基质；ii) 通过生物打印引入基底膜涂层的导管样结构；iii) 诱导进展、侵袭和导管癌血管生成在芯片上重现了体内的此类过程；iv) 建立用于抗癌药物筛选的传感器集成平台；以及 v) 扩展到肿瘤和多器官芯片平台用于全身药物效应的概念验证研究，该平台的功效将在“动物（小鼠）患者”中得到验证。 这一创新平台预计将在未来通过应用患者来源的细胞构建个性化芯片方面产生临床变革。