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

用于手术切除侵袭性脑肿瘤的新型分子成像剂

• 批准号: 9363032
• 负责人: SUSANN M BRADY-KALNAY
• 金额: $ 66.29万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-06-15 至 2022-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9363032
• 关键词: 3-Dimensional; Acids; Aminolevulinic Acid; Binding; Biodistribution; Blood - brain barrier anatomy; Brain; Brain Neoplasms; Cancerous; Cell Adhesion Molecules; Cell surface; Chemicals; Cleaved cell; Clinical; Clinical Trials; Collaborations; Conduct Clinical Trials; Cyclic GMP; Data; Development; Diffuse; Doctor of Medicine; Dose; Drug Kinetics; Effectiveness; Europe; European; Excision; FDA approved; Fluorescence; Fluorescent Dyes; Glioblastoma; Goals; Government; Grant; Guidelines; Histopathology; Human; Image; Individual; Industrialization; Inflammatory; Intravenous; Investigation; Label; Malignant Neoplasms; Malignant neoplasm of brain; Maximum Tolerated Dose; Microglia; Microscope; Microscopy; Molecular; Molecular Biology; Mus; National Comprehensive Cancer Network; Neurosurgeon; Normal tissue morphology; Operative Surgical Procedures; Patients; Performance; Pharmacodynamics; Phase; Primary Brain Neoplasms; Production; Protein Fragment; Protein Tyrosine Phosphatase; Proteolysis; Quality Control; Rare Diseases; Recurrence; Rodent; Safety; Sensitivity and Specificity; Surgeon; Testing; Time; Tissues; Toxic effect; Toxicology; Translating; Translations; Tumor Burden; Tumor Tissue; Work; Xenograft Model; Xenograft procedure; base; cancer cell; chemoradiation; clinical imaging; experience; extracellular; fluorescence imaging; imaging agent; imaging biomarker; imaging capabilities; imaging study; improved; in vivo; industry partner; meetings; millimeter; molecular imaging; neoplastic cell; neurosurgery; next generation; novel; pre-clinical; programs; receptor; reconstruction; safety testing; standard of care; survival outcome; time use; tumor; tumor microenvironment; uptake; virtual

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.

项目摘要 胶质母细胞瘤（GBM）是最常见的原发性脑肿瘤， 年手术切除可提高所有肿瘤患者的生存率，但成功切除具有挑战性 因为GBM肿瘤弥漫性浸润脑，这导致>90%的局部复发。发展 下一代荧光分子成像剂帮助外科医生区分癌细胞和正常细胞 术中组织移植将有助于降低局部复发率并改善患者的生存结果。没有 用于GBM引导手术切除的这些药剂目前已获得美国FDA批准。 细胞表面粘附分子PTPµ的细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酶解切割产生 磷酸酶（PTPµ），一种在多种肿瘤类型（包括GBM）中观察到的蛋白水解。一种与之结合的物质 PTPµ片段SBK 2识别人类GBM肿瘤。SBK 2试剂的全身递送导致结合 在啮齿类动物的原位异种移植物中， 肿瘤细胞距离体内小鼠脑中的主要肿瘤块几毫米远。 该提案旨在将这种高度选择性的荧光SBK 2试剂用于术前全身性化疗。 递送到癌性GBM组织，并通过适用于 标准荧光滤光片。荧光SBK 2分子成像剂将提高疗效， 通过允许关于肿瘤边界的实时决策来提高GBM手术的效率。 在这个学术-工业合作伙伴关系中，一个拥有分子生物学，神经外科和 分子成像监管批准，将共同努力，将SBK 2从临床前转化为临床 剂为了实现这一目标，该团队将需要进行cGMP合成和毒理学研究， 获得FDA监管机构批准用于研究用途。在FDA批准后，cGMP SBK 2试剂将 在GBM手术切除期间的0期eIND成像试验中进行测试，以确定安全性特征， 成像效能我们预计SBK 2显像剂的这一转化计划将产生新的临床应用。 为外科医生最终用户提供成像能力，以减少肿瘤负担并延长患者生存期。