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.
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.
