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.

项目总结/文摘