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

7.项目摘要/摘要 目前迫切需要改善恶性原发脑肿瘤患者的预后。根据 SEER和CBTRUS：中枢神经系统肿瘤患者的中位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之一，远远低于总和 所有癌症的生存率为67.2%。这种患者预后缺乏改善的原因不是缺乏 新的发现，但由于在将这些知识转化为临床益处方面的成功有限。长期的 我们的研究目标是将新的体内分子成像方法翻译到神经肿瘤学中，以便于 早期诊断，指导治疗，监测治疗。人异柠檬酸脱氢酶(IDH)基因突变 胶质瘤提供了极好的诊断和治疗机会，以改善患者的预后。IDH突变是 与胶质瘤高度相关，因为它们是：1)早期驱动基因突变，2)严格定位于肿瘤细胞内， 包括肿瘤干细胞，3)多见于胶质瘤患者，4)有较好的预后。因此，一个 能够对患者的IDH突变进行特异性成像的方法将对肿瘤的评估产生积极的影响 首次诊断时和后续治疗随访期间的负担。特别是确定了三个 浸润性肿瘤和侵袭性细胞克隆的维度范围是最具挑战性的问题之一， 在许多情况下，解释了由于次优治疗而导致的治疗失败。突变株的诊断和监测 IDH胶质瘤可以改善，因为代谢产物2-羟基戊二酸(2HG)作为一种 IDH突变的非常特异的生物标志物。这个应用程序的目标是开发整个大脑 定量2HG显像在突变型IDH胶质瘤诊断、治疗指导和监测中的应用。中环 我们建议的假设是活体3D磁共振波谱的技术改进 磁共振成像(MRSI)可以显著地将定量2HG成像的临床应用扩展到更大的群体 突变的IDH胶质瘤患者，并为他们提供精准医学。将实现三个具体目标，以 实现这一目标：1)开发用于突变型idh胶质瘤2HG成像的全脑3d mrsi；2)开发绝对 从全脑3D MRSI定量2HG水平，以及3)验证全脑2HG成像和绝对 突变型idh胶质瘤患者的定量研究。这项拟议研究的一个强有力的理由是，别无选择 体内成像方法对IDH突变具有特异性，而2HG编辑的MRSI是完全无创的，安全的， 可重复使用，无风险，快速，性价比高。这些优势也可以与分子和 基因分析依赖于活组织检查，对胶质瘤来说风险和成本都很高。这种方法是创新的，因为 它采用了第一个可用的活体3D成像方法来处理2HG，这一方法将在此期间得到显著改进 项目。拟议研究的贡献将是重大的，因为它将为临床医生提供 突变型IDH胶质瘤的有效诊断、规划、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.