MR Imaging of IDH Mutational Status in Brain Tumors

描述（由申请人提供）：本项目的目标是开发一种基于超极化13 C磁共振波谱（MRS）的方法，通过检测突变体IDH产生的癌代谢产物2-羟基戊二酸（2-HG）的合成，无创评估异柠檬酸脱氢酶（IDH）的突变状态和活性。动机：IDH酶的突变最近被报道在超过70%的低级别胶质瘤和继发性胶质母细胞瘤（GBM）以及23%的急性髓性白血病患者和一些结肠癌和前列腺癌病例中。野生型IDH催化异柠檬酸氧化脱羧为戊二酸（α-KG），而突变型IDH催化α-KG转化为2-HG。由于2-HG可能参与介导肿瘤发生，因此提出通过抑制突变IDH来防止其积累作为新的治疗方法。IDH突变状态和活性的非侵入性成像对于这种疗法的开发和临床实施至关重要。此外，当考虑到目前可用的疗法时，GBM中2-HG的存在与一组具有更好结果并从较低侵袭性治疗中获益的患者相关。因此，IDH状态成像将有助于将GBM患者分层为分子亚型并优化其治疗。迄今为止，IDH突变和2-HG积累仅通过高度侵入性的方法检测到，包括提取和分析活检样品。使用高分辨率魔角旋转1H MRS，最近在胶质瘤患者活检中检测到2-HG。然而，由于2-HG的复杂光谱模式及其与邻近代谢物的重叠，通过1H MRS在体内检测2-HG仍然是一个挑战。因此，需要提供IDH突变状态信息的非侵入性成像生物标志物用于患者分层和实施疾病适当的治疗。假设：我们假设IDH的突变状态可以通过使用超极化的13 C MRS探测α-KG转化为2-HG来监测。我们将通过以下目的来检验这一假设：目的1。验证超极化[1- 13 C]-alpha-KG作为分子成像剂用于使用细胞中的13 C MRS监测突变IDH活性。我们将使用13 C MRS和超极化[1- 13 C]-α-KG来监测野生型和突变型IDH细胞中α-KG向2-HG的转化。目标2.验证目标1中开发的方法作为体内原位脑肿瘤中确定IDH状态的方法。我们将研究野生型和突变IDH原位脑肿瘤，以确认目标1中开发的方法在体内研究中的价值。 公共卫生相关性：拟议的研究将解决目前未满足的对非侵入性成像方法的需求，以监测新发现的癌症相关IDH突变，该突变催化新型癌代谢物2-HG的合成。这种类型的创新成像将提供一种工具，以帮助优化专门针对肿瘤基因型的治疗方案，并为携带IDH突变的患者提供更个性化的护理。

DESCRIPTION (provided by applicant): The goal of this project is to develop a hyperpolarized 13C magnetic resonance spectroscopy (MRS)- based approach for noninvasive assessment of the mutational status and activity of isocitrate dehydrogenase (IDH) by detecting synthesis of the oncometabolite 2-hydroxyglutarate (2-HG), which is produced by mutant IDH. Motivation: Mutations in IDH enzymes were recently reported in over 70% of low grade gliomas and secondary glioblastomas (GBM) as well as in 23% of acute myeloid leukemia patients and some cases of colon and prostate cancer. Whereas wild type IDH catalyzes the oxidative decarboxylation of isocitrate to ¿- ketoglutarate (alpha-KG), mutant IDH catalyzes the conversion of alpha-KG into 2-HG. Because 2-HG is likely involved in mediating oncogenesis, preventing its accumulation by inhibiting mutant IDH was proposed as a novel therapeutic approach. Noninvasive imaging of IDH mutational status and activity is critical for development and clinical implementation of such a therapy. Furthermore, when considering currently available therapies, the presence of 2-HG in GBM is associated with a group of patients that has better outcomes and benefits from less aggressive treatment. Imaging IDH status would thus serve to stratify GBM patients into molecular subtypes and optimize their treatment. To date, IDH mutations and 2-HG accumulation have only been detected by highly invasive methods involving extraction and analysis of biopsy samples. Using high-resolution magic angle spinning 1H MRS, 2-HG was recently detected in glioma patient biopsies. However, detection of 2-HG by 1H MRS in vivo remains a challenge, due to the complex spectral pattern of 2-HG and its overlap with neighboring metabolites. Noninvasive imaging biomarkers that inform on the mutational status of IDH are therefore needed for patient stratification and implementation of disease-appropriate treatments. Hypothesis: We hypothesize that the mutational status of IDH can be monitored by probing the conversion of alpha-KG into 2-HG using hyperpolarized 13C MRS. We will test this hypothesis through the following aims: Aim 1. To validate hyperpolarized [1-13C]-alpha-KG as a molecular imaging agent for monitoring mutant IDH activity using 13C MRS in cells. We will use 13C MRS and hyperpolarized [1-13C]-alpha-KG to monitor conversion of alpha-KG into 2-HG in wild type and mutant IDH cells. Aim 2. To validate the approach developed in Aim 1 as a method for determining IDH status in orthotopic brain tumors in vivo. We will investigate wild type and mutant IDH orthotopic brain tumors to confirm the value of the approach developed in Aim 1 for in vivo studies. PUBLIC HEALTH RELEVANCE: The proposed research will address the currently unmet need for a noninvasive imaging method to monitor the newly identified, cancer-associated, IDH mutation, which catalyzes the synthesis of the novel oncometabolite 2-HG. This type of innovative imaging will provide a tool to help optimize therapeutic regimens that are specifically tailored to the tumor genotype and result in more personalized care for patients harboring IDH mutations.