Studying the Biology of IDH-mutant Gliomas Via Longitudinal Observation of 2-hydroxyglutarate (2-HG) Using MR Spectroscopy

Background:

• Glioma is the most common malignant brain tumor. Genes coding for isocitrate dehydrogenase (IDH), a metabolic enzyme, are frequently mutated in gliomas, particularly lower-grade gliomas (LGGs). IDH mutation causes a unique tumor biology, including the accumulation of 2-hydroxyglutarate (2-HG), an oncometabolite, which in turn causes genomic hypermethylation and tumorigenesis.
• Despite having a better prognosis compared to their IDH WT counterparts, IDH-mutant LGGs undergo a slow but unremitting higher-grade transformation (HT) and eventually become high grade gliomas (HGGs). A subset of patients with transformed HGGs develop a hypermutator phenotype (HMP), possibly related to previous treatment with alkylating agents. The timeline for the development of HT and HMP is unpredictable and there is no known way to prevent them from happening, largely due to a lack of understanding their biological mechanisms and lack of a non-invasive approach for potential early detection.
• Metabolic imaging, including proton magnetic resonance spectroscopy (MRS) and hyperpolarized (HP) 13C-Pyruvate MRSI, can safely detect the in vivo metabolic changes in humans.
• This clinical study will allow a longitudinal monitoring of participants with IDH-mutant gliomas for detection of disease progression, which is associated with metabolic alterations, provide an unprecedented opportunity for biopsy of the tumor for diagnostic confirmation and interrogation of the mechanisms of HT and HMP, and potentially providing a specific treatment approach for HMP which has been refractory to conventional brain tumor treatments.

Objective:

To detect and monitor the quantitative levels of 2-HG and lactate/pyruvate ratio longitudinally in participants with IDH-mutant gliomas via proton MRS and HP 13C pyruvate MRSI, respectively

Eligibility:

• Participant has glioma harboring IDH1 or IDH2 mutation confirmed by DNA sequencing.
• Age >=18 years, KPS >= 70%

Design:

• This is a prospective observational study. We will recruit up to 270 eligible participants in the next 5 years.
• The relationship between the occurrence of HT and the changes in 2-HG level and the ratio of lactate/pyruvate will be evaluated using the proportional hazard model with the latter as the time-dependent covariates.

• INCLUSION CRITERIA:
• Participants must have histologically confirmed diffuse glioma with documented IDH1 or IDH2 mutation, confirmed by DNA sequencing the exception will be participants with brain lesions that are not safe for biopsy but clinically suspected to be diffuse glioma are allowed to enroll to the study to receive imaging study as part of the exploratory study
• Participants must have measurable disease.
• Age >=18 years. Tumor biology of IDH-mutant gliomas are different in pediatric tumors. Therefore, children will be excluded from the study.
• Karnofsky performance >= 70%.
• Participants must have documented normal kidney function as defined below:

Creatinine within normal institutional limits

OR

Creatinine clearance >60 mL/min/1.73 m2 for Participants with creatinine levels above institutional normal (Measured or calculated creatinine clearance

-Participants must have adequate liver function as defined below:

total bilirubin <=2x ULN (ULN 1.3 mg/dl) except for participants with Gilbert Syndrome

AST < 3x ULN (ULN 34U/L)

ALT < 3x ULN (ULN 55U/L)

-Ability of participants to understand and the willingness to sign a written informed consent document indicating that they are aware of the investigational nature of this study, and that this is not a therapeutic clinical trial.

Exclusion criteria

• Participants who have contraindication to MRI examination, including, but not limited to, unable to receive gadolinium, medical instability, or any contraindication on MR Screening Form. Pregnant individuals are excluded because MRI contrast, planned to be used on this study, may be dangerous for the fetus. Because there is an unknown but potential risk for adverse events in nursing infants secondary to using of MRI contrast, breastfeeding should be discontinued for 72 hours following study imaging.
• Participants weighing > 350 lbs. (weight limit for scanner table), or unable to fit within the imaging gantry
• Poorly controlled hypertension, with blood pressure >150/90 mmHg.
• Congestive heart failure with New York Heart Association (NYHA) status > 2.
• A medical history of clinically significant EKG abnormalities, including QT prolongation, a family history of prolonged QT interval syndrome, or myocardial infarction (MI) less than 1 year ago with ensuing unstable EKG.
• Ongoing acute or chronic pulmonary bronchospastic disease, including a history of chronic obstructive pulmonary disease or asthma with an exacerbation within the past year.