Using MRS Imaging of a Biomarker to Assess Brain Tumor Treatments and Prognoses
Robert J. Young, M.D., and Ingo K Mellinghoff, M.D.
Memorial Sloan-Kettering Cancer Center, New York, NY, Department of Radiology, Department of Neurology
David Mahoney Neuroimaging Program
September 2014, for 3 years
Using MRS imaging of a biomarker to assess brain tumor treatments and prognoses
Investigators will advance a new MR spectroscopy (MRS) imaging technique in patients to provide fast and reliable indicators of deadly brain tumor progression and response to experimental treatments.
Brain tumors may be malignant or benign. Malignant tumors, called “gliomas,” are formed from “glial” cells in the brain that surround and support nerve cells. Gliomas—despite surgery, radiation and medical treatments—usually kill within a year as cancerous cells metastasize to other parts of the brain.
A key to personalized treatment approaches that may improve diagnosis, treatment assessment and prognosis may rest with a metabolite called “2HG.” It is produced early in tumor development by a mutant enzyme (mIDH) found in about 80 percent of low grade gliomas. The 2HG metabolite is thought to be the primary driver of cancer cell growth by inhibiting important regulatory enzymes in the brain. Since 2HG is only produced by mIDH tumors, its presence or absence is a biomarker for diagnosing malignant glioma. Moreover, determining how much 2HG is present can be used to predict tumor mutation status and to assess the effectiveness of various experimental anti-tumor treatments aimed at curtailing metastases.
Currently, though, the 2HG metabolite is identified and quantified after a patient’s surgery, when the tumorous tissue removed is tested in the laboratory. Testing can take two weeks, precious time lost in a rapidly fatal disease. Instead, the investigators hypothesize, their newly evolving MRS imaging techniques to quantify concentrations of metabolites in a patient’s brain, combined with improved tissue analyses techniques, will lead to better informed treatment decisions that help to improve chances of survival. They plan to use this biomarker in a study they are beginning to undertake of a drug designed, based on their research, to inhibit the mIDH enzyme that produces this cancer-driving metabolite.
After enrolling 120 patients with glioma in the study, investigators first will improve the spatial resolution of MRS to enable detection of even tiny gliomas in the brain. Next they will compare the MRS measurements to those obtained from the patient’s surgically removed tissue using a “solid-state” MRS technique, to further refine quantification of MRS measures. With accurate measurement, they will be able to assess the effects of the experimental therapy in reducing the 2HG metabolite and thereby reducing metastases. While the investigators will use this improved MRS technique to assess this experimental therapy’s effectiveness, the technique will have broad application to testing myriad experimental therapies designed to limit 2HG’s actions.
Additionally, the investigators will develop the capacity to improve estimates of a patient’s prognosis. They will do this by comparing a patient’s MRS measurements to those seen in “tissue banks” of deceased patients, where tissue that had been surgically removed over time from a patient is accompanied by information on that patient’s clinical course and outcome.
Significance: Development of a metabolite biomarker using MRS imaging is expected to lead to improved diagnosis, treatment and prognosis of deadly gliomas.
Quantification of 2-Hydroxyglutarate (2HG) in Mutant Isocitrate Dehydrogenase (mIDH) Tumors
IDH Mutations in Gliomas: At 80%, mutations in isocitrate dehydrogenase (IDH) represent the most common genetic alterations in World Health Organization Grade (WHO) Grade II/III human gliomas. Mutant IDH (mIDH) confers a new ability to produce the unique “oncometabolite” R-2-hydroxyglutarate (2HG). By accumulating to very high levels in mIDH tumors, 2HG is thought to be the primary effector of tumorigenesis by competitively inhibiting >50 enzymes involved in gene regulation and cellular differentiation. Since 2HG is only produced by mIDH tumors, the presence or absence of 2HG can be used to accurately predict IDH mutation status and provide useful diagnostic and prognostic information. Directly measuring 2HG is also an attractive strategy to make treatment decisions and evaluate treatment response as new mIDH inhibitors enter clinical trials. 2HG MR Spectroscopy: The 2HG molecule has five nonexchangeable scalar-coupled protons that give rise to multiplet spectroscopy resonances at 4.02 ppm (H2), 2.25 ppm (H4, H4’) and 1.9 ppm (H3, H3’) (Fig 1B.). These peaks, in particular the peak at 2.25 ppm, are amenable to measurement by MR spectroscopy (MRS). MRS is a special MR sequence that allows the quantification of different metabolite levels in vivo. Therefore, MRS offers the ability to non-invasively quantify 2HG in order to determine mIDH status and to determine the efficacy of antitumor treatments. mIDH Inhibitors Enter Clinical Trials: Given its frequency and early occurrence in the development of many tumors, mIDH presents a promising new drug target with new mIDH inhibitors entering clinical trials. Work by the Mellinghoff lab at MSKCC showed that mIDH1 selective inhibitors can impair the growth of mIDH glioma cells and promote their differentiation. Perhaps the most exciting and immediately impactful use of our methodology will be its inclusion as an exploratory biomarker into the first-in-human clinical trials with mIDH1 inhibitors now open at MSKCC. A Phase I mIDH1 inhibitor (AG-120, Agios Pharmaceuticals) trial opened in May 2014 at MSKCC (IRB #14-068, PI: Mellinghoff) for mIDH1 gliomas and other solid tumors. This inhibitor offers a promising new specific treatment option for patients with mIDH tumors, in light of the encouraging 85% response rate reported for a Phase I mIDH2 inhibitor (AG-221, Agios Pharmaceuticals) trial (MSKCC IRB #13-154, PI: Stein) presented at the American Association for Cancer Research, April 2014. Precision Imaging Biomarker for Precision Medicine: 2HG MRS represents an important potential imaging biomarker for mIDH tumors. Precision medicine is the incorporation of established clinical and pathological indices with next generation molecular profiling to personalize diagnostic, prognostic and therapeutic treatments specific to the tumor’s mutations. The 2HG oncometabolite presents a truly unique opportunity for precision medicine – where a patient can be identified as having a specific mIDH tumor, receive specific treatment in the form of an mIDH inhibitor (in clinical trials open today), and undergo specific imaging and quantification with MRS of the 2HG product of mIDH. We believe that developing robust, sensitive and specific techniques for in vivo and ex vivo 2HG quantification will facilitate informed treatment decisions and therefore contribute to improved survival.
Robert J. Young, M.D., and Ingo K Mellinghoff, M.D.
Robert J Young, M.D., is the Director of 3T MRI Neuroradiology in the Neuroradiology Service of the Department of Radiology at Memorial Sloan Kettering Cancer Center. He is a neuroradiologist whose research interests lie in the development and application of advanced MR imaging in patients with brain tumors to improve their diagnosis, prognosis, and treatment management. A member of the Functional MRI Laboratory, he has led several radiogenomic projects to explore the potential links between imaging and genomic phenotypes, including EGFR and MGMT mutations in glioblastoma. His translational research works to integrate data from the newest technologies directly into patient care decisions. His recent work has concentrated on developing MR spectroscopy techniques to allow the identification and quantification of the 2HG oncometabolite in IDH mutation gliomas.
Ingo K Mellinghoff, M.D., is the Evnin Family Chair in Neuro-Oncology and Vice Chair for Research in the Department of Neurology at Memorial Sloan Kettering Cancer Center. He is a practicing neuro-oncologist whose research program focuses on the identification and functional characterization of genetic alterations in primary human brain tumors. His research has resulted in the discovery of missense mutations in the EGFR extracellular domain in glioblastoma, the identification of PTEN loss as a major determinant of clinical EGFR kinase inhibitor resistance, and the elucidation of oncogenic properties of the mutant IDH enzyme in glioma. He has led investigator-initiated clinical trials following up on these observations.
Together, Drs. Young and Mellinghoff have built a strong research team with multiple collaborators from Neuroradiology, Neuro-Oncology, Medical Physics (co-PI: Sunitha Thakur, PhD), Neurosurgery, Neuropathology and Cell Metabolism. Their innovative efforts seek to develop and deliver personalized medicine to transform the care of glioma patients.