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.

项目概要/摘要 高级别浆液性卵巢癌 (HGSOC) 是最致命的妇科恶性肿瘤，通常是 发生远处转移后才被诊断出来，而化疗耐药性使当前的治疗效果短暂。 该领域存在两个主要的知识差距：我们缺乏对早期病变和发展的了解 新的抗癌药物。由于对最常见的问题存在争议，HGSOC 很难进行研究和建模。 起源细胞，现在被认为是输卵管上皮 (FTE)，并且因为月经 周期在 HGSOC 发展中发挥着重要作用。以前不存在这种疾病的模型，其中包括 输卵管和卵巢都能够重现人类的月经周期。 FemKube，第一个 女性生殖道芯片是通过多机构合作创建的 伊利诺伊大学西北分校和德雷珀实验室支持初级人类输卵管组织和 小鼠卵巢被设计用于驱动生理上准确的 28 天人类月经周期 微流体流动的设置。我们将利用这项创新技术来解决该领域的这两个问题： 利用它来研究输卵管的早期致癌事件并增强临床前研究 开发一种有前途的新型天然产物化疗药物——叶下珠素（PHYs）。 我们的协作团队已经证明了 FemKube 支持人类输卵管生长的能力 准确再现月经周期长度的组织。假设 FTE 已损坏 由卵巢在卵泡期（月经周期的前半段）产生的分泌因子 包括卵泡成熟），在体内分泌的孕激素的影响下恢复 黄体（排卵后卵泡的剩余部分）处于黄体后期（月经周期的后半段）。 我们的首要目标是通过绘制 DNA 图谱来研究循环卵巢如何影响 FTE 中 HGSOC 的启动 损伤、增殖和凋亡。我们将使用月经周期激素和新生激素的抑制剂 致癌介质，例如已知的 DNA 突变体、炎症和生长因子、活性氧 中和剂和肿瘤抑制剂，以机械方式研究 FemKube 系统中 HGSOC 的启动。 我们的第二个目标旨在将我们在 FemKube 中培养原代人体组织的能力结合起来 系统进入临床前药物开发管道。在我们俄亥俄州立大学合作者的帮助下 大学，我们开发了一类有前景的化合物，源自天然产物 PHY， 体外 HGSOC 细胞系的纳摩尔效力。我们将确认PHY的细胞凋亡和抗癌能力 体外。我们将在 FemKube 系统中展示它们对离体肿瘤的功效，并对我们的研究结果进行基准测试 对照小鼠体内化疗试验的金标准。总体来说，FemKube的介绍 技术将回答以前无法回答的有关 HGSOC 启动的问题并增强药物 开发管道，从而解决当前卵巢癌研究的关键差距。