Exploring PSMA Biology in Tumor neovasculature

探索肿瘤新生血管中的 PSMA 生物学

• 批准号: 9380403
• 负责人: Jan Grimm
• 金额: $ 63.19万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-06 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380403
• 关键词: Angiogenesis Inhibitors; Architecture; Biological; Biology; Biomedical Engineering; Blood group antigen S; Carboxypeptidase; Cell Culture System; Cells; Coculture Techniques; Contrast Media; Data; Development; Devices; Drug Targeting; Endothelial Cells; Evaluation; FDA approved; FOLH1 gene; Fibroblasts; Imagery; Impairment; Implant; In Vitro; Injectable; Institutes; Knockout Mice; Lasers; Lead; Malignant Neoplasms; Malignant neoplasm of prostate; Membrane Proteins; Mesenchymal; Methods; Microfluidic Microchips; Microfluidics; Mission; Molecular Profiling; Monitor; Mus; Neoplasm Metastasis; Neoplasms in Vascular Tissue; Outcome Study; Pathway interactions; Patients; Pericytes; Play; Prostate; Public Health; Research; Resistance; Resolution; Role; Scanning; Side; Solid Neoplasm; System; Testing; Time; Tumor Angiogenesis; Tumor Biology; Tumor Markers; United States National Institutes of Health; Vascularization; angiogenesis; bioimaging; cancer imaging; cancer therapy; expectation; experimental study; folic acid supplementation; imaging modality; implantation; improved; in vivo; in vivo imaging; inhibitor/antagonist; innovation; innovative technologies; insight; intravital microscopy; matrigel; monocyte; multidisciplinary; neoplastic cell; neovascularization; neovasculature; novel; novel therapeutics; overexpression; photoacoustic imaging; prototype; spatiotemporal; targeted agent; therapeutic target; therapy development; tool; tumor; tumor growth; tumor microenvironment

Abstract: Since angiogenesis is one of the hallmarks of cancer, antiangiogenic therapies have been explored as a strategy for cancer therapy. Unfortunately, with current therapies, half of the patients do not respond at all, and only every third patient gains a survival benefit. New insights into the biology of tumor neovasculature are therefore urgently needed to improve antiangiogenic therapy. We apply a multidisciplinary bioengineering approach to explore a new promising target for antiangiogenic therapy. By integrating novel tools for in vitro evaluations and in vivo imaging, we are able to gain unprecedented insight into the biological role of prostate- specific membrane antigen (PSMA) in tumor vessels. The expression of PSMA in tumor neovasculature was already described 19 years ago, yet still little is known about its biological role. We hypothesize that PSMA plays an essential role in angiogenesis of tumor vessels and is therefore a potentially promising therapeutic target. [Our preliminary data has shown that active, angiogenic endothelial cells as well as pericytes expressed high levels of PSMA] and that inhibition of PSMA's enzymatic activity severely impaired the formation of new vessels. Here, we are pairing our new biological insight with innovative technologies to further explore the role of PSMA in tumor neovasculature toward a new antiangiogenetic therapy. To examine the biological role of PSMA in tumor vessels, we will utilize significant bioengineering advancements that will allow us to make direct observations that were previously not possible: (i) A novel cell culturing system for the visualization of PSMA expression over time in EC [and co-cultured other cells such as pericytes; (ii) A prototype microfluidic system to grow a fully vascularized tumor on a chip, allowing us to directly observe the role of PSMA in tumor vascularization; and (iii) A prototype high-resolution optoacoustic scanner to globally interrogate the vasculature and molecular signatures (such as PSMA) in a developing tumor in vivo. Using these tools, developed by a unique consortium of distinctive experts, we will obtain valuable insights into tumor angiogenesis that were not previously possible. Ultimately, we will explore PSMA inhibition as a promising antiangiogenic therapy. We propose to test our hypothesis with three specific aims: In Aim 1, we will explore the role of PSMA in angiogenesis with a new culture method and the microfluidic chip system. We will assess the interplay of PSMA with other markers of angiogenesis and evaluate PSMA inhibition to impair angiogenesis. In Aim 2, we will use the new optoacoustic scanner to explore the role of PSMA in a living, developing tumor. In Aim 3, we will explore the inhibition of PSMA as a novel anti-angiogenetic therapy and monitor tumor development with optoacoustic imaging. Ultimately, this proposal will lead not only to a deeper understanding of PSMA biology but also to a new anti-angiogenetic therapy approach for cancer. [We will also have established novel methods to study tumor vasculature and the tumor microenvironment in a unique way.]

摘要：由于血管生成是癌症的标志之一，抗血管生成疗法已被探索。 作为癌症治疗的策略。不幸的是，使用目前的疗法，一半的患者根本没有反应， 只有三分之一的患者获得生存获益。对肿瘤新生血管生物学的新见解是 因此迫切需要改进抗血管生成治疗。我们应用多学科生物工程 方法探索抗血管生成治疗的新的有希望的靶点。通过整合体外新工具 评估和体内成像，我们能够对前列腺的生物学作用获得前所未有的了解 肿瘤血管中的特异性膜抗原（PSMA）。肿瘤新生血管中 PSMA 的表达 19 年前就已有描述，但对其生物学作用仍知之甚少。我们假设 PSMA 在肿瘤血管生成中发挥重要作用，因此是一种潜在有前途的治疗方法 目标。 [我们的初步数据表明，活跃的血管生成内皮细胞以及周细胞表达高 PSMA 水平]并且抑制 PSMA 酶活性严重损害新血管的形成。 在这里，我们将新的生物学见解与创新技术相结合，进一步探索 PSMA 的作用 在肿瘤新血管系统中寻找新的抗血管生成疗法。 为了研究 PSMA 在肿瘤血管中的生物学作用，我们将利用重要的生物工程 这些进步将使我们能够进行以前不可能的直接观察：（i）一种新的细胞 用于可视化 EC 中 PSMA 表达随时间变化的培养系统 [以及共培养其他细胞，例如 周细胞； (ii) 原型微流体系统，可在芯片上生长完全血管化的肿瘤，使我们能够直接 观察PSMA在肿瘤血管化中的作用； (iii) 原型高分辨率光声扫描仪 全面询问体内正在发育的肿瘤的脉管系统和分子特征（例如 PSMA）。 使用这些由独特专家组成的独特联盟开发的工具，我们将获得以下方面的宝贵见解： 以前不可能实现的肿瘤血管生成。最终，我们将探索 PSMA 抑制作为一种 有前景的抗血管生成疗法。我们建议通过三个具体目标来检验我们的假设：在目标 1 中，我们将 通过新的培养方法和微流控芯片系统探索PSMA在血管生成中的作用。我们将 评估 PSMA 与其他血管生成标志物的相互作用，并评估 PSMA 抑制对损伤的影响 血管生成。在目标 2 中，我们将使用新型光声扫描仪来探索 PSMA 在生活中的作用， 正在发展的肿瘤。在目标 3 中，我们将探索抑制 PSMA 作为一种新型抗血管生成疗法， 通过光声成像监测肿瘤的发展。最终，该提案不仅将导致更深入的 了解 PSMA 生物学，同时也了解一种新的癌症抗血管生成治疗方法。 [我们也会 建立了以独特方式研究肿瘤脉管系统和肿瘤微环境的新方法。]