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

描述(由申请人提供)：我们鉴定了一种唯一的侵袭性胶质瘤细胞标志物，该标志物源于PTP5裂解。我们开发了一种特定的分子成像探针，它结合到切割的PTP5片段上，并识别胶质母细胞瘤。因此，我们将测试该探针标记高级别人脑胶质瘤并定义侵袭性肿瘤边缘的假设。我们将探索其作为诊断分子显像剂和治疗药物的用途。原发脑瘤通常源于中枢神经系统内的神经胶质细胞的支持。这些肿瘤被称为胶质瘤，通常广泛散布在大脑各处，因此不可能进行完全的手术切除。胶质瘤的侵袭性导致很难确定其侵袭程度，并使这种疾病几乎无法治愈，平均生存时间约为一年。PTP5是一种细胞表面受体蛋白酪氨酸磷酸酶(RPTP)，是一种细胞黏附分子，在人脑胶质瘤中表达下调。最近的数据表明，在PTP5下调的过程中，蛋白质被蛋白质降解，一小部分片段仍然与胶质母细胞瘤细胞有关。在这里，我们描述了利用一种独特的强大的分子成像探针来检测PTP5片段并在体内测试其有效性的研究。我们的假设是，该探针将在细胞水平上检测迁移和侵袭的胶质母细胞瘤，并最终可用于人类患者通过磁共振成像(MRI)对肿瘤进行成像。识别关键的分子靶点，如PTP5，将允许开发新的策略来诊断、成像和最终治疗胶质瘤。可以预见，该探头还可以在手术中用于指导肿瘤的神经外科手术，从而实现更完整和精确的肿瘤切除，这将提高患者的存活率。目的1：探讨PTP5裂解片段与不同类型、不同级别人脑胶质瘤侵袭性的相关性。目的2：在体外脑片侵袭实验中，评价多肽探针在监测迁移的胶质瘤细胞中的作用。目的：在啮齿类动物的异位和原位人脑肿瘤模型中，检测该探针在体内检测肿瘤和胶质瘤细胞迁移的有效性。公共卫生相关性：我们确定了一种唯一的侵袭性胶质瘤细胞的标记，可以在体内进行分子成像。我们建议进一步表征这一独特的标志物，并探索其作为诊断分子显像剂和治疗药物的用途。我们假设该探针将在细胞水平上检测迁移和侵袭的胶质母细胞瘤，因此，该探针可以用于人类患者对侵袭性胶质瘤进行磁共振成像(MRI)。

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).