Targeting Determinants of OvCa Metastases in Engineered 3D Microfluidic Platforms

工程 3D 微流控平台中针对 OvCa 转移的决定因素

• 批准号: 9231536
• 负责人: Imran Rizvi
• 金额: $ 24.9万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-03-01 至 2019-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9231536
• 关键词: Abdomen; Abdominal Cavity; Academy; Accounting; Adipocytes; Award; Beds; Biocompatible Materials; Biologic Characteristic; Biological; Biological Markers; Biological Response Modifier Therapy; Biology; Cancer Biology; Cancer Model; Cause of Death; Cell Proliferation; Cells; Characteristics; Clinical; Combined Modality Therapy; Cues; Development; Dimensions; Dose; E-Cadherin; Endothelial Cells; Engineering; Epidermal Growth Factor Receptor; Fatty acid glycerol esters; Feedback; Female Genital Neoplasms; Fibroblasts; Fractals; Goals; Greater sac of peritoneum; Growth; Gynecologic; Health; Image; Institute of Medicine (U.S.); Integrins; Intervention; Investigation; Libraries; Light; Liquid substance; Malignant Neoplasms; Malignant neoplasm of ovary; Mentors; Mentorship; Mesothelial Cell; Microfluidic Microchips; Microfluidics; Modality; Modeling; Molecular; Molecular Target; Morphology; Neoplasm Metastasis; Nodule; Omentum; Operative Surgical Procedures; Optics; PUVA Photochemotherapy; Pathologist; Peritoneal; Peritoneum; Phase; Protocols documentation; Publishing; Research; Role; Route; Serous Membrane; Site; Stream; System; Therapeutic; Tissue Engineering; Tissues; Training; Tumor Biology; United States; United States National Academy of Sciences; Vimentin; base; cancer cell; career; cell motility; cytotoxic; design; fluorescence imaging; hydrodynamic flow; hydrodynamic model; imaging biomarker; improved; improved outcome; inhibitor/antagonist; insight; macrophage; meetings; member; model design; novel therapeutic intervention; optical imaging; professor; screening; shear stress; targeted treatment; therapeutic target; three dimensional cell culture; treatment response; treatment strategy; tumor; tumor progression

DESCRIPTION (provided by applicant): Ovarian cancer (OvCa) is the leading cause of deaths from gynecologic malignancies, and disseminates predominantly along ascitic currents in the peritoneum. The role of fluidic streams as modulators of OvCa metastatic progression and biomarker expression remains poorly explored. Models that capture critical biological and physical determinants of OvCa growth and treatment response are needed to enhance the translational potential of new therapeutic strategies. It is increasingly evident that no single treatment will be curative for metastatic OvCa. Rationally-designed combinations that impact multiple targets will most likely improve outcomes. Specifically, photodynamic therapy (PDT), a light-based cytotoxic modality, synergizes with chemo- and biological therapies. However, rapidly identifying treatments that cooperatively improve efficacy from the vast library of candidate interventions is not feasible with current systems. The goal of this proposal is to integrate microfluidics with heterocellular 3D OvCa models to create the first system to evaluate the effects of fluid hydrodynamics on OvCa progression. As a clear and distinct path to independence, Dr. Rizvi will use this platform to design therapeutic strategies uniquely based on flow-induced changes in molecular target expression. During the mentored K99 phase, OvCa cells will be cultured under precisely controlled laminar flow in microfluidic channels with tissue constructs that mimic common metastatic sites (omentum and peritoneum). Corresponding heterocellular 3D OvCa models will be developed in the absence of flow to gain insights into quantitative optical imaging of biomarker expression, 3D tumor modeling, and design of targeted therapies. Dr. Rizvi's transition to independence in the R00 phase will focus first on quantifying flow-rate dependent changes in OvCa growth and molecular target profiles. Lastly, targeted therapies informed by flow- induced changes in molecular expression will be evaluated in combination with PDT. The K99/R00 mechanism will enable development of the first treatment screening platform to model the influence of fluid hydrodyamics on OvCa metastases. The resulting platform will be applicable to a broad array of tumors with differential dissemination routes. A mentoring committee has been assembled to guide Dr. Rizvi's research and facilitate his transition to independence. Primary mentorship will be provided by Dr. Utkan Demirci, who will train Dr. Rizvi in principles of fluid dynamics and engineering of microfluidic devices. Dr. Tayyaba Hasan, an expert in quantitative biomedical optics, rationally-designed targeted therapies and 3D tumor models will serve as co- mentor. There is a notable addition to the mentoring committee in Dr. Patricia Donahoe, Dean of the DoD Ovarian Cancer Academy, a member of the National Academy of Sciences and the Institute of Medicine, and a tenured Professor of Surgery at Harvard. Additional distinguished mentors are Dr. David Kaplan, an expert in biomaterials and tissue engineering, Dr. Sandra Orsulic, an expert in the molecular characteristics of OvCa and Dr. Esther Oliva, a clinical pathologist focused on gynecologic malignancies. The opportunities provided by this award will allow Dr. Rizvi to pursue this potentially ground-breaking research, and will provide valuable mentorship to enable his successful transition to an independent and productive scientific career.

描述（由申请人提供）：卵巢癌（OVCA）是妇科恶性肿瘤死亡的主要原因，并主要沿着腹膜中的腹电流传播。流体流作为OVCA转移性进展和生物标志物表达的调节剂的作用仍然很差。需要捕获OVCA生长和治疗反应的关键生物学和身体决定因素的模型，以增强新的治疗策略的翻译潜力。越来越明显的是，没有一种治疗能够治愈转移性OVCA。影响多个目标的合理设计的组合很可能会改善结果。具体而言，光动力疗法（PDT）是一种基于光的细胞毒性方式，与化学和生物学疗法协同作用。但是，迅速识别出从候选人干预库中提高疗效的治疗方法对当前系统不可行。该建议的目的是将微流体与杂细胞3D OVCA模型相结合，以创建第一个评估流体流体动力学对OVCA进展影响的系统。作为通往独立性的明确而独特的途径，Rizvi博士将使用此平台来设计基于流动诱导的分子靶表达的变化的治疗策略。在指导的K99阶段，OVCA细胞将在与组织的微流体通道中精确控制的层流中进行培养 构造模仿常见转移性位点（脑膜和腹膜）。在没有流动的情况下，将开发相应的杂细胞3D OVCA模型，以洞悉生物标志物表达，3D肿瘤建模和靶向疗法的设计的定量光学成像。 Rizvi博士在R00阶段向独立性的过渡将首先集中于量化OVCA生长和分子靶标谱的依赖性变化。最后，将与PDT结合评估流量诱导的分子表达变化所告知的靶向疗法。 K99/R00机制将使第一个治疗筛查平台开发，以建模流体水动物学对OVCA转移的影响。所得平台将适用于具有差分传播路线的广泛肿瘤。一个指导委员会已组建，以指导Rizvi博士的研究，并促进他向独立的过渡。主要的指导将由Utkan Demirci博士提供，他将培训Rizvi博士的流动动力学和微流体设备的工程原理。 Tayyaba Hasan博士是定量生物医学光学，合理设计的靶向疗法和3D肿瘤模型的专家。在国防部卵巢癌学院的院长帕特里夏·多纳霍（Patricia Donahoe）博士，美国国家科学院和医学研究所的成员以及哈佛终身的外科教授。其他杰出的导师是生物材料和组织工程专家David Kaplan博士，Sandra Orsulic博士，他是OVCA分子特征的专家和Esther Oliva博士，Esther Oliva博士是一名临床病理学家，专注于妇科恶性肿瘤。该奖项提供的机会将使Rizvi博士能够从事这项潜在的突破性研究，并将提供宝贵的指导，以使他成功过渡到独立和生产的科学职业。