Clinical Development of Cancer-Specific MRS Biomarkers in Malignant Gliomas

Malignant gliomas represent the majority of primary brain tumors in adults and are among the
most intractable tumors. Cancers reprogram their metabolism to meet the needs of rapid cell
growth. Alterations in metabolite abundance may serve as biomarkers of malignancy, and the
capability to monitor the changes non-invasively would have significant clinical utility in
cancer. Gliomas often contain a specific metabolic activity that is predictive of the
genotype and has predictive value with respect to tumor stage and patient survival. A high
fraction of gliomas contain mutations in the metabolic enzymes, isocitrate dehydrogenase
(IDH) 1 and 2. These heterozygous mutations are confined to the active site of the enzyme and
result in a neomorphic activity that causes the mutant enzyme to produce an "oncometabolite",
2-hydroxyglutarate (2HG). Non-invasive identification of this onco-metabolite by MRS is
therefore a major breakthrough in cancer research. Beyond simple detection of 2HG, our
preliminary data show that 2HG is a remarkably sensitive biomarker for monitoring tumor
progression and response to treatment in IDH mutated gliomas. Glycine (Gly) is a biomarker of
tumor malignancy, as indicated in prior studies. Our data also indicate that citrate (Cit) is
elevated in gliomas.

Over the course of this preliminary study, there has been crucial need for 3D evaluation of
these onco-metabolites within the tumor mass. The Investigators will examine the clinical
utility of 2HG, Gly and Cit, in a large cohort of subjects using multi-slice 2D MRSI at 3T.
The specific aims include, first, an in-vivo MRS study for the disease specificity of 2HG
(Aim 1). The Investigators will examine clinically proven non-glioma lesions that mimic
glioma in clinical MRI. To increase the clinical applicability of the result, the
Investigators will select non-enhancing brain diseases, given that IDH mutation occurs
largely in grade-2 and -3 gliomas, which are often non-enhancing. Second, the Investigators
will examine the clinical utility of 2HG, Gly, Cit and other metabolites in patients with IDH
mutated gliomas (Aim 2). Third, the Investigators will examine the clinical utility of Gly,
Cit and other metabolites in patients with IDH wild type gliomas (Aim 3). In Aim 2 and 3, the
patients will undergo MRSI scans at multiple time points, and the Investigators will monitor
the metabolic changes with tumor progression and in response to treatment. The Investigators
anticipate our study will provide significant value in many aspects of management of gliomas.
3D evaluation of the cancer biomarkers using MRSI will provide biological insights for making
the diagnosis of gliomas, tracking of infiltrative cells during follow up, and determining
response to treatment. Success of the 2HG specificity study in non-glioma neurological
diseases will provide an experimental evidence for use of non-invasive 2HG imaging as a
triaging tool in the workup of a new brain mass.

Inclusion Criteria:

Patients with brain tumors (55 subjects):

- Age > 18 years

- Males and females

- All races and ethnicity

- Patients must meet at least one of the 3 following criteria regarding brain tumor
diagnosis:

- Histological diagnosis of a brain tumor

- Pre-operative brain MR imaging suggestive of a brain tumor

- Radiographic diagnosis of brain tumor in an inoperable location (e.g. brainstem)

- Pretreatment evaluation required for eligibility include a medical history, physical
examination, and neurological exam within 30 days prior to study entry.

- Patient must be able to provide study-specific consent prior to study entry and Health
Insurance Portability and Accountability Act of 1996 (HIPAA) authorization.

Karnofsky performance status > 70%

Patients with non-tumor neurological disorders (50 subjects):

- Males and females

- All races and ethnicities

- Patients with clinically-proven encephalitis (infections, autoimmune and
paraneoplastic), demyelinating lesions, vascular lesions (subacute arterial infarct,
venous infarct, and vasculitis), hamartomatous lesions, and malformations of cortical
development.

Exclusion Criteria:

- Age under 18*.

- Cardiac pacemaker.

- Intracranial clips, metal implants, or external clips within 50 cm from the head.

- Metal in eye.

- Pregnancy.

- Claustrophobia.

- Obesity or any other factors that provide difficulty with supine pose in the magnet.

- Patients who are unable to provide informed consent.

- Patients who are pregnant or nursing.

- Patients with severe kidney dysfunction or uncontrolled cardiac dysfunction.

- Patients who are claustrophobic or have other contraindication to MRI, such as
implanted pacemaker device, vascular cips, surgical slips, prosthetic valves,
pacemakers, otologic implants.

- Patients with uncontrolled psychiatric manifestations of their brain tumor.

- Children (age < 18) are excluded from the study plan because the incidence of
astrocytomas and glioblastoma in children is far less than in adults. Although
children frequently develop brain tumors, the glial tumors are most often pilocytic
astrocytomas. In addition, enrollment of adults will be beneficial for the MRS
sequence validation tests in healthy subjects since adults can remain motionless
during the MR scans compared to children, giving minimal motion artifacts om the MR
data.