Development of whole-brain in vivo 2HG imaging for precision medicine in mutant IDH glioma

7.项目概要/摘要 迫切需要改善恶性原发性脑肿瘤患者的预后。根据 SEER和CBTRUS将CNS癌症患者的中位5年生存率从32.3%提高到34.4% 在过去的二十年里，这是成人恶性肿瘤中最低的，也低于联合国儿童基金会的报告。 所有癌症的存活率为67.2%。患者结局缺乏改善不能解释为缺乏 新发现，但由于将这些知识转化为临床益处的成功有限。长期 我们的研究目标是在神经肿瘤学中转化新的体内分子成像方法， 早期诊断、指导治疗和治疗监测。异柠檬酸脱氢酶（IDH）突变 神经胶质瘤提供了巨大的诊断和治疗机会，以改善患者的结果。IDH突变是 与神经胶质瘤高度相关，因为它们是：1）早期驱动突变，2）严格位于肿瘤细胞内， 包括癌症干细胞，3）经常存在于胶质瘤患者中，4）具有更好的预后。因此，A 一种可以特异性成像患者IDH突变的方法将对评估肿瘤 在初次诊断和后续治疗随访期间的负担。特别是，确定三个 浸润性肿瘤和侵袭性细胞克隆的尺寸范围是最具挑战性的问题之一， 并且在许多情况下解释了由于次优治疗导致的治疗失败。突变体的诊断和监测 IDH神经胶质瘤可以改善，因为代谢物2-羟基戊二酸（2 HG）的大量积累， IDH突变的特异性生物标志物。本申请的目的是开发全脑 定量2 HG成像用于突变IDH胶质瘤的诊断、治疗指导和监测。中央 我们提出假设是活体3D磁共振波谱技术的改进 磁共振成像（MRSI）可以显着扩展定量2 HG成像的临床效用，以更大的一组 突变IDH神经胶质瘤患者，并为他们提供精准医疗。将实现三个具体目标， 实现这一目标：1）开发全脑3D MRSI用于突变IDH胶质瘤的2 HG成像，2）开发绝对的 从全脑3D MRSI定量2 HG水平，以及3）验证全脑2 HG成像和绝对2 HG水平。 在突变IDH胶质瘤患者中进行定量。拟议研究的一个强有力的理由是， 体内成像方法对IDH突变是特异性的，而2 HG编辑的MRSI是完全非侵入性的，安全的， 可以重复使用，没有风险，快速且具有成本效益。这些优点也与分子和分子生物学相比很好。 遗传分析依赖于活检，风险和成本都很高。这种方法是创新的，因为 它采用了第一种用于2 HG的体内3D成像方法，这将在此期间得到显着改进。 项目这项拟议研究的贡献将是重大的，因为它将为临床医生提供一个 是突变IDH胶质瘤有效诊断、计划、指导和监测工具。

7. Project Summary/Abstract There is an urgent need to improve outcomes of patients with malignant primary brain tumors. According to SEER and CBTRUS the median 5-year survival rate for CNS cancer patients improved from 32.3% to 34.4% over the last twenty years, which is among the lowest in adult malignancies and well bellow the combined survival rate of 67.2% for all cancers. This lack of improvement in patient outcomes is not explained by lack of new discoveries, but due to limited success in translating this knowledge into clinical benefit. The long-term goal of our research is translation of new in vivo molecular imaging methods in neuro-oncology to facilitate early diagnosis, guided therapy and treatment monitoring. Mutations of isocitrate dehydrogenase (IDH) in glioma offer great diagnostic and therapeutic opportunities to improve patient outcomes. IDH mutations are highly relevant for glioma because they are: 1) early driver mutations, 2) localized strictly within tumor cells, including cancer stem cells, 3) frequently present in glioma patients, 4) have better prognostic. Hence, a method that can specifically image IDH mutations in patients will have the positive impact to assess tumor burden at the initial diagnosis and during subsequent treatment follow up. In particular, determining the three dimensional extent of infiltrative tumors and aggressive cell clones is one of the most challenging problems, and in many cases explains treatment failure due to suboptimal therapy. Diagnosis and surveillance of mutant IDH glioma can be improved because of large accumulation of the metabolite 2-hydroxyglutarate (2HG) as a very specific biomarker for IDH mutations. The objective in this application is to develop whole brain quantitative 2HG imaging for diagnosis, treatment guidance and monitoring of mutant IDH glioma. The central hypothesis of our proposal is that technical improvement of in vivo 3D magnetic resonance spectroscopic imaging (MRSI) can significantly extend the clinical utility of quantitative 2HG imaging to a larger group of mutant IDH glioma patients and enable precision medicine for them. Three specific aims will be performed to achieve this goal: 1) develop whole-brain 3D MRSI for 2HG imaging of mutant IDH glioma, 2) develop absolute quantification of 2HG levels from whole-brain 3D MRSI, and 3) validate whole-brain 2HG imaging and absolute quantification in mutant IDH glioma patients. A strong rationale for the proposed research is that no alternative in vivo imaging method is specific for IDH mutations, while 2HG edited MRSI is completely non-invasive, safe, can be repeated without risks, fast and cost effective. These advantages compare well also to molecular and genetic analysis relying on biopsies with great risks and costs for glioma. The approach is innovative because it employs the first available in vivo 3D imaging method for 2HG, which will be significantly improved during this project. The contribution of the proposed research will be significant because it will provide clinicians with an effective diagnostic, planning, guiding and monitoring tool for mutant IDH glioma.