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

描述（由申请人提供）：我们鉴定了由PTP 5切割产生的侵袭性胶质瘤细胞的独特标志物。我们开发了一种特异性的分子成像探针，它可以结合裂解的PTP 5片段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类胶质瘤并定义侵入肿瘤边缘的假设。我们将探索其作为诊断分子成像剂和治疗剂的效用。原发性脑肿瘤通常来自中枢神经系统内的支持神经胶质细胞。这些肿瘤被称为神经胶质瘤，通常广泛分布在整个大脑中，使得完全手术切除是不可能的。胶质瘤的侵袭性导致难以确定侵袭程度，并使这种疾病几乎无法治愈，平均生存期约为一年。PTP 5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，其在人类胶质瘤中表达下调。最近的数据表明，在PTP 5下调期间，蛋白质被蛋白水解，并且小片段仍然与胶质母细胞瘤细胞相关。在这里，我们描述的研究，利用一个独特的强大的分子成像探针的PTP 5片段，并测试其在体内的有效性。我们的假设是，该探针将在细胞水平上检测迁移和侵入的胶质母细胞瘤，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。关键分子靶标如PTP 5的鉴定将允许开发新的策略来诊断、成像并最终治疗胶质瘤。据设想，该探针还可以在手术期间用于引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：确定PTP5切割片段与各种类型和级别的人类胶质瘤侵袭性的关联程度。目的2：评估肽探针在离体脑切片侵袭测定中监测迁移的胶质瘤细胞的效用。目标3：检查探针在啮齿动物异位和原位人脑肿瘤模型中体内检测肿瘤和迁移性胶质瘤细胞的效用。 公共卫生相关性：我们发现了一种独特的入侵胶质瘤细胞的标记物，可以在体内进行分子成像。我们建议进一步表征这种独特的标记物，并探索其作为诊断分子成像剂和治疗剂的效用。我们假设该探针将在细胞水平检测迁移和侵袭性胶质母细胞瘤，因此，该探针可用于人类患者的磁共振成像（MRI）成像侵袭性胶质瘤。

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).