IDH1-targeted fluorescence guided surgery of low grade glioma

点击翻译按钮获取中文摘要

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.