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

描述（由申请人提供）：我们发现了一种独特的胶质瘤细胞入侵标记，该标记来自PTP5切割。我们开发了一种特殊的分子成像探针，可以结合裂解的PTP5片段并识别胶质母细胞瘤。因此，我们将验证该探针标记高级别人类胶质瘤并确定入侵肿瘤边缘的假设。我们将探讨其作为诊断分子显像剂和治疗的效用。原发性脑肿瘤通常是由中枢神经系统内的支持神经胶质细胞引起的。这些肿瘤被称为神经胶质瘤，通常分散在整个大脑，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的程度，使这种疾病几乎无法治愈，平均生存期约为一年。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，在人胶质瘤中表达下调。最近的数据表明，在PTP5下调过程中，该蛋白被蛋白水解，并且一小部分仍与胶质母细胞瘤细胞相关。在这里，我们描述了利用一种独特的强大的PTP5片段分子成像探针并测试其体内有效性的研究。我们的假设是，该探针将在细胞水平上检测到胶质母细胞瘤的迁移和侵袭，并最终可用于人类患者的肿瘤磁共振成像（MRI）成像。识别关键分子靶点，如PTP5，将有助于开发诊断、成像和最终治疗胶质瘤的新策略。展望该探针还可用于手术指导肿瘤的神经外科手术，使肿瘤切除更完整、更精确，提高患者生存率。目的1：确定PTP5断裂片段与不同类型和等级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试验中监测迁移胶质瘤细胞的效用。目的3：研究探针在啮齿动物异位和正位人脑肿瘤模型中检测肿瘤和迁移胶质瘤细胞的效用。公共卫生相关性：我们确定了一种独特的入侵胶质瘤细胞标记物，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，并探索其作为诊断分子显像剂和治疗的效用。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，该探针可用于人类患者的核磁共振成像（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).