IDH1-targeted fluorescence guided surgery of low grade glioma

摘要： 低级别胶质瘤（LGG）是弥漫性浸润性脑肿瘤，不成比例地影响年轻人。左 未经治疗的这些肿瘤具有由肿瘤进展，致残性神经症状， 最终导致死亡手术在其管理中起着至关重要的作用。LGG大体全切除术（GTR） 对生存产生深远影响，为年轻患者提供数十年的额外优质生活。总计的值 切除术是公认的，但不幸的是只有15%的低级别胶质瘤手术发生。这些 肿瘤缺乏典型地用于识别肿瘤的显著特征，例如肿瘤坏死或血管分布增加 肿瘤和正常组织之间的边界经常由于它们的扩散而模糊。 浸润在LGG中提高大体全切除率的努力很少，主要集中在 高级别肿瘤使用MRI的术中图像引导的先进方法是资源密集型的， 然而，超声等其他标准技术通常不适用于LGG。 使用5-氨基乙酰丙酸（ALA）的荧光引导手术（FGS）已经显示出巨大的前景， 被广泛使用。ALA在手术前给药，并优先转化为荧光抗体。 化合物原卟啉IX在肿瘤细胞中提供正常组织和肿瘤之间的可见对比。虽然 FGS明显使HGG患者受益，但在低级别胶质瘤的情况下仍然无效。小于 三分之一的LGG与5-ALA一起显示任何可见荧光，即使诊断准确性很差， 当使用先进的荧光成像定量方法时。替代荧光剂 研究依赖于存在破坏的血脑屏障或与LGG无关的受体。 我们概述了一个创新的策略，荧光引导手术在低级别胶质瘤，利用独特的 这些肿瘤的分子生物学，以开发一种新的靶向药物。一个保守的突变（R132H）， 蛋白质异柠檬酸脱氢酶（IDH）在超过80%的低级别胶质瘤中发现，而与亚型无关。 IDH的突变驱动肿瘤形成，并且在整个肿瘤中发现高水平的突变蛋白。 由于这些原因，IDH（R132H）突变是理想的治疗靶点，并且许多小分子化合物可以用于治疗。 抑制剂最近已进入临床试验。我们建议构建一种荧光IDH成像剂， 现有的小分子抑制剂和新的合成化学。我们假设这种荧光剂 将高度靶向IDH突变型低级别肿瘤，在手术过程中提供可见的对比度， 对这些患者的生存有着深远的影响。

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.