Targeting Determinants of OvCa Metastases in Engineered 3D Microfluidic Platforms

描述(申请人提供)：卵巢癌(OvCa)是妇科恶性肿瘤死亡的主要原因，主要沿腹膜腹水扩散。流体流作为OvCa转移进展和生物标记物表达的调节器的作用仍未被充分了解。需要捕捉OvCa生长和治疗反应的关键生物学和物理决定因素的模型，以增强新治疗策略的翻译潜力。越来越明显的是，任何单一的治疗方法都不能治愈转移性OvCa。影响多个目标的合理设计的组合最有可能改善结果。具体地说，光动力疗法(PDT)是一种基于光的细胞毒疗法，与化学和生物疗法协同作用。然而，在目前的系统中，从庞大的候选干预措施库中快速确定合作提高疗效的治疗方法是不可行的。该方案的目标是将微流体学与异质细胞3D OvCa模型相结合，创建第一个评估流体动力学对OvCa进展的影响的系统。作为一条明确和独特的独立途径，里兹维博士将利用这一平台，根据流动诱导的分子靶标表达的变化，独特地设计治疗策略。在指导的K99阶段，OvCa细胞将在精确控制的层流中与组织一起在微流体通道中培养 模拟常见转移部位(大网膜和腹膜)的结构。在没有血流的情况下，将开发相应的异质细胞3D OvCa模型，以深入了解生物标记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阶段向独立性的过渡将首先专注于量化OvCa生长和分子靶标图谱中与流速相关的变化。最后，通过流动诱导的分子表达变化提供信息的靶向治疗将与光动力疗法结合起来进行评估。K99/R00机制将使第一个治疗筛选平台的开发成为可能，以模拟流体流体动力学对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的肿瘤。一个指导委员会已经成立，以指导里兹维博士的研究，并促进他向独立的过渡。主要导师将由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设备工程方面的培训。塔亚巴·哈桑博士是定量生物医学光学、合理设计的靶向疗法和3D肿瘤模型方面的专家，他将担任共同导师。指导委员会中还有一位值得注意的新成员，帕特里夏·多纳霍博士，他是美国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，哈佛大学终身外科学教授。其他杰出的导师包括生物材料和组织工程专家大卫·卡普兰博士、卵巢癌分子特征专家桑德拉·奥苏利克博士和专注于妇科恶性肿瘤的临床病理学家埃丝特·奥利瓦博士。该奖项提供的机会将使里兹维博士能够从事这一潜在的开创性研究，并将提供宝贵的指导，使他能够成功地过渡到独立和多产的科学事业。

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.