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Pre-clinical evaluation of copper-64-bevacizumab as a new positron emission tomography tumor detection probe.

机译：临床前评估铜-64-贝伐单抗作为一种新的正电子发射断层扫描肿瘤检测探针。

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摘要

Cancer is one of the leading causes of deaths in the U.S. and worldwide. One of the main obstacles for early detection and treatment of cancer is the lack of sensitive and tumor-specific probes. Currently, 18F-Fluorodeoxyglucose (18FDG) positron emission tomography (PET) imaging is one of the most common and powerful techniques in clinical use to detect and stage cancer. However, the result is only satisfactory on limited tumor types and can be associated with confusing false-positive findings. Angiogenesis, the formation of new blood vessels, is a common prerequisite for the development of a broad range of tumors and cancer metastases. Vascular endothelial growth factor (VEGF) is the most dominant pro-angiogenic factor and it's the only growth factor that has been found to be expressed throughout the whole tumor life cycle for a wide range of cancer types including metastasis. The goal of this project was to develop and validate a new generation of PET imaging biomarker (64Cu-bevacizumab) by targeting the VEGF released from cancer related tissue in order to not only accurately detect tumor in an earlier stage compared with 18FDG but also effectively decrease the false positive findings shown in 18FDG imaging.;The hypothesis of this project was that radiolabeled anti-VEGF antibody (64Cu-bevacizumab) could be used as a PET marker to detect a wide range of tumor types and metastasis at an earlier stage than 18FDG. And because of the difference in the physiological uptake mechanism with 18FDG, we also hypothesized that 64Cu-bevacizumab imaging will have fewer false-positive findings than 18FDG imaging and could effectively detect a broad range of tumors and metastasis in nude mice models.;The specific aims of this project were to (1) develop a chemical method to radiolabel anti-VEGF antibody, Bevacizumab, and the control antibody with 64Cu, achieving predefined radiochemical properties, good immunoreactivity, and in vitro stability; (2) to understand the pharmacokinetics, biodistribution and imaging properties of 64Cu-bevacizumab by performing studies in established pancreatic cancer xenograft and orthotopic mouse models (Mia Paca-2) and compare the result with standard 18FDG imaging; (3) to verify the generalizability of 64Cu-bevacizumab on tumor detection by performing microPET/CT imaging studies and evaluating the biodistribution and imaging properties in different cancer xenograft and orthotopic mouse models and compare the result with standard 18FDG imaging (BxPC3, H460, CACO-2, MDA-MB-231, LNCaP, and SKOV3); (4) to evaluate the ability and sensitivity of 64Cu-bevacizumab to detect metastatic tumor by performing microPET/CT imaging studies and evaluating the biodistribution and imaging properties in a breast cancer bone metastasis mouse model (MDA-MB-231) and compare the result with standard 18FDG imaging.;The conclusions of this study are 64 Cu-bevacizumab showed its superiority in tumor detection in 7 different human cancer mouse xenograft, orthotopic, and metastatic models over 18FDG. Experiment results demonstrated that 64Cu-bevacizumab can detect tumor earlier than 18FDG and showed fewer false positive findings in a series of pre-clinical studies. Since bevacizumab is a FDA approved drug, the results suggest that to apply this probe to human use for this purpose is highly possible. If so, this would result in early treatment and may possibly increase survival rate to various cancers.
机译：癌症是美国和世界范围内主要的死亡原因之一。癌症的早期发现和治疗的主要障碍之一是缺乏灵敏且肿瘤特异性的探针。当前，18 F-氟脱氧葡萄糖（18FDG）正电子发射断层扫描（PET）成像是临床上用于检测和分期癌症的最常见，最强大的技术之一。然而，该结果仅在有限的肿瘤类型上令人满意，并且可能与令人困惑的假阳性结果相关。血管生成，即新血管的形成，是广泛的肿瘤和癌症转移发展的普遍前提。血管内皮生长因子（VEGF）是最主要的促血管生成因子，也是唯一被发现在包括转移在内的多种癌症的整个生命周期中都表达的生长因子。该项目的目标是通过靶向从癌相关组织释放的VEGF，开发和验证新一代PET成像生物标记物（64Cu-贝伐单抗），以便不仅与18FDG相比可以更早地准确检测肿瘤，而且可以有效地降低该项目的假设是，与18FDG相比，放射性标记的抗VEGF抗体（64Cu-bevacizumab）可以作为PET标记物在更早的阶段检测多种肿瘤类型和转移。并且由于18FDG的生理摄取机制不同，我们还假设64Cu-贝伐单抗成像比18FDG成像具有更少的假阳性结果，并且可以有效地检测裸鼠模型中的多种肿瘤和转移。该项目的目的是（1）开发一种化学方法，以放射性标记抗VEGF抗体贝伐单抗和带有64Cu的对照抗体，以达到预定的放射化学特性，良好的免疫反应性和体外稳定性。 （2）通过在已建立的胰腺癌异种移植和原位小鼠模型（Mia Paca-2）中进行研究，了解64Cu-贝伐单抗的药代动力学，生物分布和成像特性，并将结果与​​标准18FDG成像进行比较； （3）通过进行microPET / CT成像研究并评估不同癌症异种移植和原位小鼠模型的生物分布和成像特性，验证64Cu-贝伐单抗在肿瘤检测中的通用性，并将结果与​​标准18FDG成像（BxPC3，H460，CACO -2，MDA-MB-231，LNCaP和SKOV3）； （4）通过进行microPET / CT成像研究并评估乳腺癌骨转移小鼠模型（MDA-MB-231）的生物分布和成像特性来评估64Cu-贝伐单抗检测转移性肿瘤的能力和敏感性，并比较结果本研究的结论是64 Cu-贝伐单抗在7种​​不同的人类癌小鼠异种移植，原位和转移模型中显示出优于18FDG的肿瘤检测优势。实验结果表明，在一系列的临床前研究中，64Cu-贝伐单抗可以比18FDG更早地检测出肿瘤，并且显示出更少的假阳性结果。由于贝伐单抗是FDA批准的药物，因此结果表明，将该探针应用于人类目的是极有可能的。如果是这样，这将导致早期治疗并可能增加各种癌症的存活率。

著录项

  • 作者

    Chang, Ting-Tung.;

  • 作者单位

    The University of Texas Health Science Center at San Antonio.;

  • 授予单位 The University of Texas Health Science Center at San Antonio.;
  • 学科 Physics Nuclear.;Biophysics Medical.;Health Sciences Oncology.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 146 p.
  • 总页数 146
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

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