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，在目前的治疗中，一半的患者根本没有反应， 只有三分之一的患者能获得生存益处。对肿瘤新生血管生物学的新认识是 因此迫切需要改进抗血管生成治疗。我们运用多学科生物工程 为抗血管生成治疗探索一个新的有希望的靶点。通过整合新的工具， 评估和体内成像，我们能够获得前所未有的洞察前列腺的生物学作用- 特异性膜抗原（PSMA）。PSMA在肿瘤新生血管中的表达 早在19年前就已经描述过，但对其生物学作用仍知之甚少。我们假设PSMA 在肿瘤血管的血管生成中起重要作用，因此是一种潜在的有前途的治疗药物 目标[Our初步数据显示，活跃的血管生成内皮细胞以及周细胞表达高水平的 PSMA水平]，并且PSMA酶活性的抑制严重损害了新血管的形成。 在这里，我们将新的生物学见解与创新技术相结合，以进一步探索PSMA的作用。 在肿瘤新生血管形成中的作用。 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技术， 这些进展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 培养系统，用于观察EC中PSMA随时间的表达[和共培养的其它细胞， 周细胞;（ii）原型微流体系统在芯片上生长完全血管化的肿瘤，使我们能够直接 观察PSMA在肿瘤血管形成中的作用;以及（iii）原型高分辨率光声扫描仪， 在体内全面询问发展中肿瘤中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： 肿瘤血管生成，这在以前是不可能的。最终，我们将探索PSMA抑制作为 有希望的抗血管生成疗法我们建议用三个具体目标来检验我们的假设：在目标1中，我们将 利用新的培养方法和微流控芯片系统探讨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抑制对血管生成的影响。 血管生成在目标2中，我们将使用新的光声扫描仪来探索PSMA在活体中的作用， 发展肿瘤。在目标3中，我们将探索抑制PSMA作为一种新的抗血管生成疗法， 用光声成像监测肿瘤发展。最终，这一提议不仅将导致更深层次的 这不仅有助于对PSMA生物学的理解，而且有助于癌症的新的抗血管生成治疗方法。[We也将 已经建立了新的方法，以独特的方式研究肿瘤血管和肿瘤微环境。