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，并且主要沿着腹膜中的腹水流传播。流体流作为 OvCa 转移进展和生物标志物表达调节剂的作用仍然很少被探索。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来增强新治疗策略的转化潜力。越来越明显的是，没有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疗法，与化学疗法和生物疗法具有协同作用。然而，在当前的系统中，从庞大的候选干预措施库中快速识别能够协同提高疗效的治疗方法是不可行的。该提案的目标是将微流体与异细胞 3D OvCa 模型相结合，创建第一个评估流体流体动力学对 OvCa 进展影响的系统。作为一条清晰而独特的独立之路，Rizvi 博士将利用该平台根据流动诱导的分子靶标表达变化来设计独特的治疗策略。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 模仿常见转移部位（大网膜和腹膜）的结构。相应的异细胞 3D OvCa 模型将在没有流动的情况下开发，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 R00 阶段向独立过渡将首先关注量化 OvCa 生长和分子靶标谱中流速依赖性变化。最后，根据血流诱导的分子表达变化通知的靶向治疗将与 PDT 结合进行评估。 K99/R00 机制将有助于开发第一个治疗筛选平台，以模拟流体流体力学对 OvCa 转移的影响。由此产生的平台将适用于具有不同传播途径的广泛肿瘤。已经成立了一个指导委员会来指导 Rizvi 博士的研究并促进他向独立过渡。主要指导将由 Utkan Demirci 博士提供，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。 Tayyaba Hasan 博士是定量生物医学光学、合理设计的靶向治疗和 3D 肿瘤模型方面的专家，他将担任导师。指导委员会中还有一位值得注意的新成员：帕特里夏·多纳霍 (Patricia Donahoe) 博士，她是国防部卵巢癌学院院长、美国国家科学院和医学研究所成员、哈佛大学外科终身教授。其他杰出导师包括生物材料和组织工程专家 David Kaplan 博士、OvCa 分子特征专家 Sandra Orsulic 博士和专注于妇科恶性肿瘤的临床病理学家 Esther Oliva 博士。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，使他能够成功过渡到独立且富有成效的科学职业。