Imaging the Glioma Biomarker 2HG
Incubating Progress: Talent + Technology + Teamwork
Imaging innovations developed by UT Southwestern scientists are deployed to improve brain cancer care
Nearly one-third of brain tumors are gliomas. These tumors can lie dormant for months or years, then suddenly start growing rapidly in a deadly form called glioblastoma.
Gliomas traditionally have been diagnosed via surgical biopsy, an invasive procedure that is especially risky when tumors are near sensitive sites in the brain. Detecting precisely when gliomas become glioblastomas is a challenge, and the transformation requires aggressive treatment. Doctors would like more information about how tumors respond to treatment and which treatments best target traits specific to individual tumors.
Building on fundamental imaging and metabolism research at UT Southwestern, Cancer Center scientists and physicians have developed innovative approaches to address these challenges.
1980s: Ongoing work at UT Southwestern, spearheaded by Drs. Dean Sherry and Craig Malloy, focuses on development of tracer molecules that can be used with magnetic resonance (MR) technology to measure changes in metabolism that occur with disease.
2007: The two researchers hone the use of carbon-13 (13C), a stable natural isotope, in a hyperpolarized state—activating its nuclei so they create a signal powerful enough to track in the body. Enriching substances such as glucose with 13C allows the researchers to better detect details of the substances’ metabolism than does current technology.
2009: Research elsewhere links cancer-associated mutations in the gene IDH1 to high levels of a metabolite called 2-hydroxyglutarate (2HG) and finds elevated 2HG in surgical samples of malignant gliomas. UT Southwestern physicist Changho Choi, Ph.D., and neuro-oncologist Elizabeth Maher, M.D., Ph.D., already working on MR spectroscopy of glioblastoma to find tumor biomarkers, focus their work on developing an approach to noninvasively detect 2HG.
2010–2012: UT Southwestern researchers including Drs. Ralph DeBerardinis, Maher, Malloy, Robert Bachoo, and neurosurgeon Bruce Mickey, M.D., pioneer the presurgery infusion of 13C-labeled glucose to directly study metabolic flux in patients with brain tumors. Once the tumors are removed, researchers use MR spectroscopy to provide a “snapshot” of the tumor cells’ metabolic processing of the glucose. The team finds that glioma cells—and metastatic lung and breast cancer cells in the brain—metabolize glucose much more rapidly than does the rest of the brain, using the energy to survive and to help perpetuate growth of new tumor cells.
2012: A team led by Drs. Choi and Maher finds 2HG is detectable with MR technology using a technique called point-resolved spectroscopy, or PRESS. Accumulation of 2HG is associated with mutations in IDH1 and 2, a hallmark of about 70 percent of gliomas. Thus, 2HG can be used as a biomarker to identify gliomas without need for surgical biopsy; the biomarker also can provide information on patient prognosis and has the potential to help track tumor progression and drug response.
2014: Infusing mouse models of human gliomas with 13C-labeled glucose and 13C-labeled acetate, a team led by Dr. Bachoo demonstrates that cancer cells can use acetate to fuel growth. The study, along with research led by Cancer Center biochemists, pinpoints ACSS2, an enzyme that metabolizes acetate, as a potential treatment target.
2014–15: Researchers launch a prospective phase I/II clinical trial, led by Dr. Maher and conducted at William P. Clements Jr. University Hospital, testing the IDH2 inhibitor AG-221 (Agios Pharmaceuticals), the first drug of its type, in patients with tumors including gliomas. Researchers deploy their approach to noninvasively measure levels of 2HG (the metabolite associated with the IDH1/2 mutation) in gliomas, providing a way to monitor drug penetration into the tumor and ability to inhibit the target.
Building on the finding that acetate can fuel cancer growth, Cancer Center scientists are revealing more about the role of ACSS2, which is expressed in a variety of human tumors, as a potential vulnerability that may be exploited therapeutically.
Based on the insights made in studying tumor metabolism in brain cancer patients at the time of surgery, several other areas of focus have emerged. Dr. DeBerardinis and colleagues are pursuing similar studies in lung cancer, and Drs. Maher and Bachoo are studying early-stage breast cancer in collaboration with Roshni Rao, M.D. They are also working with pediatric neurosurgery and neuro-oncology teams to address many of the same metabolic questions in childhood brain cancers.
Dr. Choi and colleagues are working to bring their MR technique for measuring 2HG in the brain—developed in research scanners at a magnetic field strength of 3 Tesla—to 3T clinical scanners, as well as to achieve 2HG detection using lower-powered (1.5T) scanners.
Drs. DeBerardinis, Malloy, Sherry, and others are working to develop imaging of hyperpolarized pyruvate and acetate to study metabolism of cancers in the body. One important goal is to understand energy production in cancers, which identifies possible vulnerabilities and the opportunity for drug targeting.
A new hyperpolarizing technology called SPINlab—funded through an award from the National Institutes of Health, along with support from UT Southwestern—will enable metabolic analyses at the cellular level in patients. By improving sensitivity of nuclear MR by a factor of 10,000 or more, hyperpolarization could help physicians determine cancer severity, identify recurrence or metastasis, gauge the impact of treatment, and better predict disease outcomes. The technique might also help guide novel therapy choices for patients based on their tumors’ individual metabolism.
Merritt, M.E. et al. Hyperpolarized 13C allows a direct measure of flux through a single enzyme-catalyzed step by NMR. Proc Natl Acad Sci U S A 104, 19773-77 (2007).
Choi, C. et al. 2-hydroxyglutarate detection by magnetic resonance spectroscopy in IDH-mutated patients with gliomas. Nat Med 18, 624-29 (2012).
Marin-Valencia, I. et al. Analysis of tumor metabolism reveals mitochondrial glucose oxidation in genetically diverse human glioblastomas in the mouse brain in vivo. Cell Metab 15, 827-37 (2012).
Maher, E.A. et al. Metabolism of 13C glucose in human brain tumors in vivo. NMR Biomed 25, 1234-44 (2012).
Sagiyama, K. et al. In vivo chemical exchange saturation transfer imaging allows early detection of a therapeutic response in glioblastoma. Proc Natl Acad Sci U S A, 111, 4542–47 (2014).
Mashimo, T. et al. Acetate is a bioenergetic substrate for human glioblastoma and brain metastases. Cell 159, 1603-14 (2014).