A Novel Molecular Imaging Agent for Surgical Resection of Invasive Brain Tumors

项目摘要 胶质母细胞瘤(GBM)是最常见的原发脑肿瘤，患者的中位生存期略高于1岁。 年。手术切除所有强化肿瘤可延长生存期，但成功的切除是具有挑战性的 由于基底膜肿瘤弥漫性地侵袭大脑，导致90%的局部复发。开发一种 帮助外科医生区分癌症和正常的下一代荧光分子显像剂 术中组织移植将有助于降低局部复发率和改善患者的生存结果。不是 这种用于引导手术切除基底膜的药物目前已获得美国FDA的批准。 细胞表面黏附分子PTPµ的胞外片段是一种独特的成像生物标志物 肿瘤微环境。PTPµ片段由受体蛋白酪氨酸的蛋白水解性切割而来 磷酸酶(PTPµ)，一种存在于多种肿瘤类型中的蛋白质分解，包括基底膜。一个与此绑定的代理 PTPµ片段SBK2可识别人的GBM肿瘤。SBK2试剂的全身给药导致结合 在啮齿类动物的原位异种移植中，几分钟内就能标记出肿瘤细胞，并几乎可以标记所有分散的脑 肿瘤细胞距离小鼠脑内的主要肿瘤块几毫米远。 这项提议旨在将这种高选择性的荧光SBK2试剂转化为手术前全身 传送到癌变的GBM组织并使其实时可见，目前的手术显微镜适应于 标准荧光滤光片。荧光SBK2分子显像剂将增强疗效和 通过允许关于肿瘤边界的实时决定来提高GBM手术的效率。 在这个学术-产业合作伙伴关系中，一个在分子生物学、神经外科和 分子成像监管批准，将共同努力将SBK2从临床前转化为临床 探员。为了实现这一目标，该团队将需要进行cGMP合成和毒理学研究之前 获得FDA监管部门的批准，用于研究用途。在FDA批准后，cGMP SBK2代理人将 在手术切除基底膜期间进行的0期EIND成像试验中进行了测试，以确定安全性和 成像效果。我们期望SBK2显像剂的这一翻译计划将产生一种新的临床 为外科医生最终用户提供成像能力，以减轻肿瘤负担和延长患者生存时间。

Project Summary Glioblastoma (GBM), the most common primary brain tumor, has median patient survival of little more than one year. Surgical resection of all enhancing tumor prolongs survival, yet successful resection is challenging because GBM tumors diffusely infiltrate the brain, which results in >90% local recurrence. Development of a next-generation fluorescent molecular imaging agent to help surgeons differentiate cancerous from normal tissue intraoperatively will help reduce the rate of local recurrence and improve patient survival outcomes. No such agent for guided surgical resection of GBM currently has US FDA approval. An extracellular fragment of the cell surface adhesion molecule PTPµ is a unique imaging biomarker of the tumor microenvironment. The PTPµ fragment arises from proteolytic cleavage of the receptor protein tyrosine phosphatase (PTPµ), a proteolysis seen in multiple tumor types including GBM. An agent that binds to this PTPµ fragment, SBK2, recognizes human GBM tumors. Systemic delivery of the SBK2 agent results in binding to tumor cells within minutes in orthotopic xenografts in rodents, and can label virtually all the dispersing brain tumor cells several millimeters away from the main tumor mass in mouse brains in vivo. This proposal aims to translate this highly-selective fluorescent SBK2 agent for pre-surgical systemic delivery to cancerous GBM tissue and render it visible in real-time by current surgical microscopy adapted with standard fluorescent filters. The fluorescent SBK2 molecular imaging agent would enhance the efficacy and efficiency of GBM surgery by allowing real-time decisions regarding tumor borders. In this Academic-Industrial Partnership, a team with expertise in molecular biology, neurosurgery and molecular imaging regulatory approval, will work together to translate SBK2 from a preclinical to a clinical agent. To achieve this goal, the team will need to perform cGMP synthesis and toxicology studies before obtaining FDA regulatory approval for investigational use. Upon FDA approval, the cGMP SBK2 agents will be tested in a Phase 0 eIND imaging trial during surgical resection of GBM for determination of safety profile and imaging efficacy. We expect that this translational plan for the SBK2 imaging agent will yield a new clinical imaging capability for surgeon end users to reduce tumor burden and prolong patient survival.