IDH1-targeted fluorescence guided surgery of low grade glioma

IDH1靶向荧光引导低级别胶质瘤手术

基本信息

批准号：
10477242
负责人：
Linton T. Evans
金额：
$ 31.28万
依托单位：
DARTMOUTH-HITCHCOCK CLINIC
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10477242
关键词：
Adoption Affect Aminolevulinic Acid Benchmarking Biological Markers Blood - brain barrier anatomy Blood Vessels Brain Brain Neoplasms Central Nervous System Neoplasms Cessation of life Clinical Clinical Trials Contrast Media Development Diagnostic Diffuse Disease Dose Evaluation Excision Exhibits Expert Opinion Fluorescence Fluorescent Dyes Glioma Growth Histology Human Image Image-Guided Surgery Imaging technology Immunohistochemistry In Vitro Indolent Infiltration Investigation Isocitrate Dehydrogenase Kinetics Lead Left Length Life Magnetic Resonance Imaging Malignant - descriptor Measures Methods Minority Groups Modeling Molecular Biology Mutate Mutation Nature Necrosis Neurologic Symptoms Neuronavigation Noise Normal tissue morphology Operating Rooms Operative Surgical Procedures Patient-Focused Outcomes Patients Performance Point Mutation Pre-Clinical Model Proteins Quality of life Reporting Resolution Resources Role Signal Transduction Specificity Subgroup Syncope Synthesis Chemistry Techniques Technology Therapeutic Toxicology Tumor Biology Tumor Tissue Validation Xenograft procedure base clinical investigation diagnostic accuracy fluorescence imaging fluorescence-guided surgery image guided imaging agent improved improved outcome in vitro Assay in vivo in vivo evaluation inhibitor innovation lead candidate mortality mutant neoplastic cell neurosurgery novel novel strategies operation protein expression protoporphyrin IX receptor receptor expression small molecule inhibitor targeted agent targeted imaging therapeutic target tumor tumor progression tumor xenograft ultrasound validation studies young adult

项目摘要

Abstract: Low grade gliomas (LGG) are diffusely infiltrative brain tumors that disproportionately affect young adults. Left untreated these tumors have a devastating course defined by tumor progression, disabling neurologic symptoms, and ultimately death. Surgery has an essential role in their management. Gross total resection (GTR) of LGG has a profound impact on survival giving young patients decades of additional quality life. The value of a total resection is well recognized, but unfortunately occurs in only 15% of surgeries for low grade glioma. These tumors lack distinctive features such as tumor necrosis or increased vascularity typically used to identify tumor to be removed, and the boundary between tumor and normal tissue is frequently blurred due to their diffuse infiltration. Efforts to improve rates of gross total resection in LGG have been sparse and largely focused on high grade tumors. Advanced methods of intraoperative image guidance using MRI are resource intensive and frequently prohibitive, while other standard technologies such as ultrasound are often inadequate for LGG. Fluorescence guided surgery (FGS) using 5-aminolevulinic acid (ALA) has demonstrated enormous promise and is in widespread use. ALA is administered prior to surgery and preferentially converted to the fluorescent compound protoporphyrin IX in tumor cells providing visible contrast between normal tissue and tumor. Although FGS has clearly benefited patients with HGG, it remains ineffective in the setting of low grade glioma. Less than one-third of LGG exhibit any visible fluorescence with 5-ALA, and the diagnostic accuracy remains poor even when using advanced quantitative methods of fluorescence imaging. Alternative fluorescent agents under investigation rely on the presence of a disrupted blood brain barrier or receptors that are not relevant in LGG. We outline an innovative strategy for fluorescence guided surgery in low grade glioma that utilizes the unique molecular biology of these tumors to develop a novel targeted agent. A conserved mutation (R132H) in the protein Isocitrate dehydrogenase (IDH) is found in more than 80% of low grade gliomas regardless of subtype. Mutation of IDH drives tumor formation, and the mutated protein is found throughout the tumor in high levels. For these reasons the IDH (R132H) mutation is an ideal therapeutic target, and a number of small molecule inhibitors have recently entered clinical trials. We propose to construct a fluorescent IDH imaging agent using existing small molecule inhibitors and novel synthetic chemistry. It is our hypothesis that this fluorescent agent will be highly targeted to IDH mutant low grade tumors providing visible contrast during surgery, and ultimately have a profound impact on survival in these patients.

抽象的：低级神经胶质瘤（LGG）是不成比例地影响年轻人的扩散性浸润性脑肿瘤。左边未经治疗的这些肿瘤具有毁灭性的病程，由肿瘤进展，使神经系统症状失败，并最终死亡。手术在其管理中起着至关重要的作用。 LGG总切除（GTR）对生存产生深远影响，使年轻患者数十年的额外质量寿命数十年。总价值切除术是众所周知的，但不幸的是，仅15％的低级神经胶质瘤手术。这些肿瘤缺乏独特的特征，例如肿瘤坏死或通常用于识别肿瘤的血管性增加要去除，并且由于肿瘤和正常组织之间的边界，由于它们的扩散而经常模糊浸润。提高LGG总切除率的努力稀疏，主要集中在高级肿瘤。使用MRI的术中图像指导的高级方法是资源密集的，并且通常过于望而却步的，而其他标准技术（例如超声）通常不适用于LGG。使用5-氨基乙烯酸（ALA）的荧光引导手术（FGS）表现出巨大的希望和在广泛使用中。 ALA在手术前施用，并优先转换为荧光肿瘤细胞中的复合原源性IX提供正常组织和肿瘤之间可见的对比度。虽然 FGS显然使HGG患者受益，在低级神经胶质瘤的情况下仍然无效。少于三分之一的LGG具有5-ALA的任何可见荧光，诊断精度仍然很差当使用荧光成像的高级定量方法时。替代荧光剂研究依赖于与LGG无关的血脑屏障或受体的存在。我们概述了低级神经胶质瘤中荧光引导手术的创新策略，该策略利用了独特的这些肿瘤的分子生物学发展了新型靶向剂。保守的突变（R132H）在超过80％的低级神经胶质瘤中发现蛋白质异戊酸脱氢酶（IDH），无论亚型如何。 IDH的突变驱动肿瘤形成，并且在整个肿瘤中发现突变的蛋白质。由于这些原因抑制剂最近进入了临床试验。我们建议使用现有的小分子抑制剂和新型合成化学。我们的假设是这种荧光剂将高度针对IDH突变体低级肿瘤，可在手术过程中提供可见的对比度，最终可见对这些患者的生存有深远的影响。