Exploring PSMA Biology in Tumor neovasculature

摘要：由于血管生成是癌症的标志之一，人们探索了抗血管生成的治疗方法。 作为癌症治疗的一种策略。不幸的是，在目前的治疗方法中，一半的患者根本没有反应， 而且只有三分之一的患者获得生存福利。对肿瘤新生血管生物学的新见解是 因此迫切需要提高抗血管生成治疗水平。我们应用了多学科的生物工程 目的探索抗血管生成治疗的新靶点。通过集成用于体外培养的新工具 评估和活体成像，我们能够对前列腺的生物学作用获得前所未有的洞察- 肿瘤血管特异性膜抗原(PSMA)。PSMA在肿瘤新生血管中的表达 19年前就已经被描述了，但对它的生物学作用仍然知之甚少。我们假设PSMA 在肿瘤血管生成中起着至关重要的作用，因此是一种有潜力的治疗方法 目标。[我们的初步数据显示，活跃的新生血管内皮细胞和周细胞高表达 PSMA水平]和抑制PSMA的酶活性严重损害了新血管的形成。 在这里，我们将我们的新生物学洞察力与创新技术相结合，进一步探索PSMA的作用 在肿瘤新生血管方面走向一种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，我们将利用有意义的生物工程。 使我们能够进行以前不可能进行的直接观察的进展：(I)一个新的细胞 培养系统，用于可视化PSMA在EC[和共培养的其他细胞，如 (Ii)在芯片上生长完全血管化的肿瘤的原型微流控系统，允许我们直接 观察PSMA在肿瘤血管形成中的作用；以及(Iii)一台原型高分辨率光声扫描仪 全球询问体内正在发展的肿瘤的血管系统和分子特征(如PSMA)。 使用这些由独特的专家组成的联盟开发的工具，我们将获得对 这是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 很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 用一种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。我们会 评估PSMA与其他血管生成标志物的相互作用，并评估PSMA的抑制作用 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在生活中的作用， 发展中的肿瘤。在目标3中，我们将探讨PSMA作为一种新的抗血管生成疗法的抑制作用和 用光声成像监测肿瘤的发展。最终，这一提议不仅将导致更深层次的 对PSMA生物学的了解，也是一种新的癌症抗血管生成治疗方法。[我们还将 建立了以独特的方式研究肿瘤血管和肿瘤微环境的新方法。]

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.]