Detecting invading glioma cells through in vivo molecular imaging of the cell sur

通过细胞表面的体内分子成像检测入侵的神经胶质瘤细胞

• 批准号: 7562871
• 负责人: SUSANN M BRADY-KALNAY
• 金额: $ 40万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-04-01 至 2014-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7562871
• 关键词: Adult; Affinity; Binding; Biological Assay; Brain; Brain Neoplasms; Cell Adhesion Molecules; Cell Surface Receptors; Cells; Characteristics; Cleaved cell; Clinical; Collaborations; Contrast Media; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Down-Regulation; Effectiveness; Excision; Exhibits; Fluorescence; Glioblastoma; Glioma; Histocytochemistry; Hour; Human; Image; Imaging Techniques; Imaging technology; Immigration; Injection of therapeutic agent; Intracranial Neoplasms; Invaded; Label; Lead; Life; Magnetic Resonance Imaging; Measures; Modeling; Molecular; Molecular Target; Monitor; Neuraxis; Neuroglia; Neurosurgeon; Operative Surgical Procedures; Patients; Peptides; Primary Brain Neoplasms; Property; Proteins; Proteolysis; Proteolytic Processing; Rodent; Sampling; Site; Slice; System; Tail; Testing; Therapeutic; Therapeutic Agents; Time; Tissues; Veins; cohort; glioma cell line; human PTPRT protein; imaging probe; in vivo; molecular imaging; neoplastic cell; neurosurgery; novel strategies; outcome forecast; public health relevance; reconstruction; research study; tumor

DESCRIPTION (provided by applicant): We identified a unique marker of invading glioma cells that arises from PTP5 cleavage. We developed a specific molecular imaging probe that binds to the cleaved PTP5 fragment and recognizes glioblastomas. Therefore, we will test the hypothesis that this probe marks high-grade human gliomas and defines the invading tumor margin. We will explore its utility as a diagnostic molecular imaging agent and as a therapeutic. Primary brain tumors commonly arise from supporting glial cells within the central nervous system. These tumors are called gliomas and typically disperse widely throughout the brain making complete surgical resection impossible. The invasive properties of gliomas lead to difficulties in determining the extent of invasion and make this disease virtually incurable with a mean survival of approximately one year. PTP5 is a cell surface receptor protein tyrosine phosphatase (RPTP) and a cell adhesion molecule whose expression is down-regulated in human gliomas. Very recent data suggests that during PTP5 down-regulation, the protein is proteolyzed and a small fragment remains associated with the glioblastoma cells. Here we describe studies that utilize a unique robust molecular imaging probe for the PTP5 fragment and test its effectiveness in vivo. Our hypothesis is that the probe will detect the migrating and invading glioblastomas at the cellular level and can eventually be used in human patients to image the tumors with magnetic resonance imaging (MRI). Identification of key molecular targets such as PTP5 will allow development of novel strategies to diagnose, image and eventually treat gliomas. It is envisioned that this probe could also be utilized during surgery to guide neurosurgery of the tumors enabling more complete and precise tumor resection, which will enhance patient survival. Aim 1: Determine the extent of association of the cleaved fragment of PTP5 with invasiveness of human gliomas of various types and grades. Aim 2: Assess the utility of peptide probes to monitor migrating glioma cells in an ex vivo brain slice invasion assay. Aim 3: Examine the utility of the probe to detect tumors and migrating glioma cells in vivo in heterotopic and orthotopic human brain tumor models in rodents. Public Health Relevance: We identified a unique marker of invading glioma cells that can be molecularly imaged in vivo. We propose to further characterize this unique marker and to explore its utility as both a diagnostic molecular imaging agent and a therapeutic. We hypothesize that the probe will detect the migrating and invading glioblastomas at the cellular level, therefore, the probe can be used in human patients to image invasive gliomas with magnetic resonance imaging (MRI).

描述（由申请人提供）：我们确定了由PTP5裂解引起的入侵神经胶质瘤细胞的独特标记。我们开发了一种特定的分子成像探针，该探针与裂解的PTP5片段结合并识别胶质母细胞瘤。因此，我们将检验以下假设：该探针标志着高级人神经胶质瘤并定义了入侵的肿瘤边缘。我们将探索其作为诊断分子成像剂和治疗性的效用。原发性脑肿瘤通常是由中枢神经系统中的支持神经胶质细胞引起的。这些肿瘤被称为神经胶质瘤，通常在整个大脑中广泛分散，使完全的手术切除不可能。神经胶质瘤的侵入性特性导致了确定侵袭程度的困难，并使这种疾病几乎无法治愈，平均存活率约为一年。 PTP5是一种细胞表面受体蛋白酪氨酸磷酸酶（RPTP）和细胞粘附分子，其表达在人神经胶质瘤中被下调。最近的数据表明，在PTP5下调期间，蛋白质是蛋白质水解，并且小片段仍然与胶质母细胞瘤细胞相关。在这里，我们描述了用于PTP5片段的独特鲁棒分子成像探针并在体内测试其有效性的研究。我们的假设是探针将检测细胞水平的迁移和入侵胶质母细胞瘤，并最终可用于人类患者中，以对具有磁共振成像（MRI）的肿瘤对肿瘤进行成像。鉴定关键分子靶标，例如PTP5，将允许开发新的策略来诊断，图像并最终治疗神经胶质瘤。可以预见的是，该探针在手术期间也可以用于指导肿瘤的神经外科手术，从而更完整，更精确，这将增强患者的生存率。 AIM 1：确定PTP5裂片片段与各种类型和等级的人神经胶质瘤的侵入性的关联程度。 AIM 2：评估肽探针在离体脑切片浸润测定法中监测迁移的神经胶质瘤细胞的效用。 AIM 3：检查探针在啮齿动物中异位和原位人脑肿瘤模型中检测体内肿瘤和神经胶质瘤细胞的效用。 公共卫生相关性：我们确定了可以在体内分子成像的入侵神经胶质瘤细胞的独特标记。我们建议进一步表征这种独特的标记，并探索其作为诊断分子成像剂和治疗性的效用。我们假设探针将检测细胞水平的迁移和入侵胶质母细胞瘤，因此，可以在人类患者中使用该探针以磁共振成像（MRI）对入侵性神经胶质瘤进行成像。