FemKube, the human female reproductive tract-on-a-chip, as a platform for studying high grade serous ovarian cancer and developing novel cancer chemotherapeutics

FemKube，人类女性生殖道芯片，作为研究高级别浆液性卵巢癌和开发新型癌症化疗药物的平台

• 批准号: 9328947
• 负责人: Alexandria Young
• 金额: $ 4.4万
• 依托单位: UNIVERSITY OF ILLINOIS AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-05-16 至 2022-05-15
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328947
• 关键词: Address; Apoptosis; Apoptotic; Benchmarking; Biological Assay; Cancer cell line; Cancerous; Cell Culture Techniques; Cell Proliferation; Cells; Clinical; Collaborations; DAB2 gene; DNA; DNA Damage; DNA mapping; Development; Devices; Diagnosis; Disease model; Distant Metastasis; Drug Compounding; Early Diagnosis; Engineering; Enzymes; Epithelium; Estrogens; Event; Female; Follicular Fluid; Gold; Growth; Growth Factor; Hormones; Human; IGF1 gene; Illinois; In Vitro; Inflammatory; Knowledge; Length; Lesion; Luteal Phase; Malignant Female Reproductive System Neoplasm; Malignant Neoplasms; Malignant neoplasm of ovary; Mammalian Oviducts; Maps; Mediating; Mediator of activation protein; Menstrual cycle; Methodology; Microfluidics; Modality; Modeling; Mus; Natural Products; Ohio; Oncogenic; Organ; Ovarian; Ovary; Ovulation; Patients; Pattern; Physiological; Play; Preclinical Drug Development; Prevention; Progestins; Reactive Oxygen Species; Research; Role; SOD2 gene; Serous; Source; System; TP53 gene; Technology; Tissues; Tumor Suppressor Proteins; Universities; Vascular Endothelial Growth Factors; Woman; anticancer research; cancer initiation; chemokine; chemotherapy; corpus luteum; drug development; fluid flow; fundamental research; human female; human tissue; in vivo; inhibitor/antagonist; innovative technologies; insight; nanomolar; novel; novel anticancer drug; preclinical development; proliferative phase Menstrual cycle; repaired; reproductive tract; response; targeted treatment; tool; tumor; tumor initiation

PROJECT SUMMARY/ABSTRACT High grade serous ovarian cancer (HGSOC), the most lethal gynecologic malignancy, is typically diagnosed after distant metastasis has occurred, and chemoresistance renders current treatments short-lived. Two major knowledge gaps exist in the field: we lack an understanding of early lesions and development of new anticancer drugs. HGSOC has been difficult to research and model due to debate over the most common cell of origin, which is now accepted to be the fallopian tube epithelium (FTE), and because the menstrual cycle plays a role in HGSOC development. No models of the disease previously existed, which incorporate both the fallopian tube and an ovary capable of recapitulating the human menstrual cycle. FemKube, the first female reproductive tract-on-a-chip, was created through a multi-institutional collaboration between the University of Illinois, Northwestern, and Draper Labs to support primary human fallopian tube tissues and murine ovaries, which are engineered to drive a physiologically accurate 28-day human menstrual cycle, in the setting of microfluidic flow. We will leverage this innovative technology to address both issues in the field by utilizing it to investigate early oncogenic events in the fallopian tube and to enhance the preclinical development of a promising new class of natural product chemotherapeutics, Phyllanthusmins (PHYs). Our collaborative team has demonstrated the ability of FemKube to support growth of human fallopian tissues for the length of an accurately reproduced menstrual cycle. It is hypothesized that the FTE is damaged by secreted factors produced by the ovary during the follicular phase (first half of the menstrual cycle that encompasses follicle maturation), which is restored under the influence of progestins secreted from the corpus luteum (what remains of the follicle after ovulation) in the late luteal phase (second half of the menstrual cycle). Our first aim is to investigate how the cycling ovary impacts HGSOC initiation in the FTE by mapping DNA damage, proliferation, and apoptosis. We will use inhibitors of menstrual cycle hormones and nascent oncogenic mediators, such as known DNA mutators, inflammatory and growth factors, reactive oxygen species neutralizers and tumor suppressors, to mechanistically study HGSOC initiation in the FemKube system. Our second aim seeks to incorporate our ability to culture primary human tissues in the FemKube system into the preclinical drug development pipeline. With the help our collaborators at the Ohio State University, we have developed a promising class of compounds derived from natural products, PHYs, with nanomolar potency on HGSOC cell lines in vitro. We will confirm PHY's apoptotic and anticancer abilities in vitro. We will demonstrate their efficacy on tumors ex vivo in the FemKube system and benchmark our findings against gold standard in vivo chemotherapeutic assays in mice. Overall, the introduction of FemKube technology will answer previously inaccessible questions on HGSOC initiation and enhance the drug development pipeline, thereby addressing key gaps in current ovarian cancer research.

项目摘要/摘要 高级浆液卵巢癌（HGSOC），最致命的妇科恶性肿瘤通常是 发生远处转移后被诊断出来，化学抗性使当前处理短暂。 该领域存在两个主要的知识差距：我们对早期病变的了解和发展 新的抗癌药。由于关于最常见的争论，HGSOC很难研究和模型 原始细胞现在被接受为输卵管上皮（FTE），并且因为月经 周期在HGSOC开发中起作用。以前没有这种疾病的模型，它包含 输卵管和能够概括人类月经周期的卵巢。 Femkube，第一个 女性生殖道是通过多机构的合作而创建的 伊利诺伊大学，西北大学和德雷珀实验室，以支持原代人输卵管组织和 在生理上精确的28天人类月经周期的设计，在该工程中进行了设计。 微流动流的设置。我们将利用这项创新技术来解决该领域的两个问题 利用它来研究输卵管中的早期致癌事件并增强临床前 开发有希望的新型天然产品化学治疗剂Phyllanthusmins（Phys）。 我们的合作团队证明了Femkube支持人类输卵管增长的能力 组织的精确再现的月经周期。假设FTE已损坏 由卵泡阶段卵巢产生的分泌因子（月经周期的前半部分） 包含卵泡成熟），它在从语料库分泌的孕激素的影响下恢复 黄体晚期（月经周期的后半部分）在黄体期（排卵后毛囊中剩下的）。 我们的第一个目的是研究循环卵巢如何通过映射DNA来影响FTE中的HGSOC启动 损害，增殖和凋亡。我们将使用月经周期激素和新生的抑制剂 致癌介质，例如已知的DNA突变器，炎症和生长因子，活性氧 中源和肿瘤抑制剂，以机械学研究女性的HGSOC启动。 我们的第二个目标旨在将我们培养原代人组织培养的能力纳入Femkube 系统进入临床前药物开发管道。在俄亥俄州立大学的帮助下 大学，我们开发了一类有希望的化合物，这些化合物来自天然产品，物理，带有 体外HGSOC细胞系上的纳摩尔效力。我们将确认Phy的凋亡和抗癌能力 体外。我们将证明它们在Femkube系统中离体肿瘤的功效，并基准我们的发现 针对小鼠的黄金标准体内化学治疗测定。总体而言，Femkube的引入 技术将回答先前有关HGSOC启动的问题并增强药物的问题 开发管道，从而解决当前卵巢癌研究中的关键差距。