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: 9236168
• 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/9236168
• 关键词: Abdomen; Abdominal Cavity; Academy; 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; Custom; Development; Dimensions; Disseminated Malignant Neoplasm; 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; Institute of Medicine (U.S.); Integrin alpha5beta1; Intervention; Investigation; Libraries; Light; Liquid substance; Malignant Female Reproductive System Neoplasm; 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; Physiological; Protocols documentation; Publishing; Research; Role; Route; Serous Membrane; Site; Stream; System; Therapeutic; Thinness; 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; member; model design; novel therapeutic intervention; optical imaging; professor; public health relevance; routine imaging; 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，主要沿腹膜中的腹水电流传播。流体流作为OvCa转移进展和生物标志物表达的调节剂的作用仍然很少探索。需要捕获OvCa生长和治疗反应的关键生物和物理决定因素的模型，以增强新治疗策略的转化潜力。越来越明显的是，没有一种单一的治疗方法可以治愈转移性OvCa。影响多个目标的合理设计的组合将最有可能改善结果。具体而言，光动力疗法（PDT），一种基于光的细胞毒性方式，与化学和生物疗法协同作用。然而，从候选干预措施的庞大库中快速识别协同提高疗效的治疗方法对于当前系统是不可行的。该提案的目标是将微流体与异细胞3D OvCa模型相结合，以创建第一个评估流体动力学对OvCa进展影响的系统。作为一个清晰而独特的独立途径，Rizvi博士将利用这个平台设计基于流动诱导的分子靶点表达变化的独特治疗策略。在指导的K99阶段，OvCa细胞将在具有组织的微流体通道中在精确控制的层流下培养。 模拟常见转移部位（网膜和腹膜）的构建体。将在没有流动的情况下开发相应的异细胞3D OvCa模型，以深入了解生物标志物表达的定量光学成像，3D肿瘤建模和靶向治疗的设计。Rizvi博士在R 00阶段向独立性的过渡将首先集中在定量OvCa生长和分子靶点分布的流速依赖性变化上。最后，将结合PDT评估由流动诱导的分子表达变化所告知的靶向治疗。K99/R 00机制将使第一个治疗筛选平台的开发成为可能，以模拟液体水肿对OvCa转移的影响。由此产生的平台将适用于广泛的肿瘤与差异传播途径。已经组建了一个指导委员会，指导Rizvi博士的研究，并协助他向独立过渡。Utkan德米尔奇博士将提供主要指导，他将对Rizvi博士进行流体动力学原理和微流体装置工程方面的培训。定量生物医学光学、合理设计的靶向治疗和3D肿瘤模型专家Tayyaba Hasan博士将担任共同导师。Patricia Donahoe博士是指导委员会的一个值得注意的成员，她是国防部卵巢癌研究院院长，国家科学院和医学研究所的成员，也是哈佛大学的终身外科教授。其他杰出的导师是生物材料和组织工程专家大卫卡普兰博士、OvCa分子特征专家桑德拉·奥苏利奇博士和专注于妇科恶性肿瘤的临床病理学家埃斯特·奥利瓦博士。该奖项提供的机会将使Rizvi博士能够从事这项潜在的开创性研究，并将提供宝贵的指导，使他能够成功过渡到独立和富有成效的科学事业。