MCBRAYER LAB

Research Focus

Alterations in whole-body metabolism, such as those that occur in obesity or diabetes, can increase the risk of developing certain forms of cancer. These findings indicate that external metabolic cues can trigger cancer formation and growth at the cellular level. However, we have limited knowledge of the internal metabolic changes that influence whether a cell becomes cancerous or not.

Our goal is to identify the metabolic mechanisms that push cells to become cancerous and find new ways to inhibit them. To identify these mechanisms, we study the biology of brain tumors driven by mutations in genes that regulate metabolism. Studying these mutations will help us discover fundamental connections between metabolism and other aspects of cell biology that are likely to control cancer formation in many different tissues. These insights hold great promise for the development of new therapies for patients with brain tumors and, by extension, for those with other types of cancer.

Research Projects

Dissecting the Molecular Cascade Linking IDH1 Mutations with Gliomagenesis

Understanding Mechanisms of Nitrogen Incorporation into the Glioma Metabolome

Exploiting Synthetic Lethality with IDH1 Mutations to Improve Brain Tumor Therapy

Dissecting the Molecular Cascade Linking IDH1 Mutations with Gliomagenesis

IDH1 mutations are the signature genetic feature of lower grade gliomas and secondary glioblastomas. They are thought to initiate gliomagenesis by causing accumulation of the oncometabolite (R)-2-hydroxyglutarate in neural progenitor cells. (R)-2-hydroxyglutarate, in turn, controls the activity of dioxygenase enzymes which regulate chromatin structure, hypoxia signaling, and other key aspects of neural cell biology. Collectively, these effects promote brain tumor initiation. Although this framework represents a significant advance in our understanding of the oncogenicity of IDH1 mutations, detailed characterization of the molecular cascades that link (R)-2-hydroxyglutarate accumulation with gliomagenesis has not been fully completed.

We are currently undertaking complementary top-down and bottom-up approaches to dissect specific oncogenic mechanisms engaged by IDH1 mutations. To systematically identify critical proximal effectors of (R)-2-hydroxyglutarate in glioma, we are performing CRISPR/Cas9 screens to uncover dioxygenases that control malignant transformation in cellular contexts that closely recapitulate glioma genetics. We are also using a novel genetically-engineered mouse model of glioma created in our laboratory to characterize the dynamics of the distal effects of mutant IDH1 on the epigenome and the transcriptome. Taken together, findings from these studies are expected to provide a comprehensive understanding of how (R)-2-hydroxyglutarate induces glial cell transformation in vivo. These findings may reveal metabolic mechanisms of transformation with relevance beyond the setting of IDH1 mutant glioma. Furthermore, our findings may reveal unappreciated therapeutic opportunities to impede brain tumor progression.

Understanding Mechanisms of Nitrogen Incorporation into the Glioma Metabolome

The paradigm of malignant transformation by IDH1 mutations holds that (R)-2-hydroxyglutarate produced by IDH1 mutant enzymes directly modulates the activity of oncogenic or tumor suppressive dioxygenase enzymes to promote tumorigenesis. Recently, we showed that (R)-2-hydroxyglutarate can also regulate the activity of another class of enzymes known as transaminases (McBrayer et al, 2018). Specifically, we found that (R)-2-hydroxyglutarate directly inhibits the branched chain amino acid transaminases BCAT1 and BCAT2. These enzymes play central roles in nitrogen metabolism in glial cells and our work revealed that (R)-2-hydroxyglutarate accumulation impairs the BCAT-dependent synthesis of nitrogenous metabolites.

These findings provide a mechanistic explanation for metabolic differences observed between IDH1 mutant and wild-type brain tumors but, at the same time, prompt fundamental questions about nitrogen metabolism programs in cancer. How do tumor cells couple the catabolism of specific amino acids to the synthesis of key nitrogenous metabolites? How do tumor cells engage compensatory amino acid catabolism pathways to adapt to nitrogen limitation? The answers to these questions have been obscured by conventional depictions of metabolic pathways from carbon-centric standpoints. We aim to answer these questions using metabolomic profiling and isotope tracing approaches in in vitro and in vivo glioma models to systematically map nitrogen metabolism pathways. These studies are expected to illuminate novel patterns of nitrogen incorporation in IDH1 mutant brain tumors as well as other cancers that display BCAT-independent metabolic phenotypes.

Exploiting Synthetic Lethality with IDH1 Mutations to Improve Brain Tumor Therapy

Malignant gliomas are notoriously refractory to therapy and there is a dire unmet need for new treatments. Discovery of the high prevalence of IDH1 mutations in lower grade gliomas and secondary glioblastomas has opened new avenues for therapeutic intervention, including the use of direct inhibitors of mutant IDH1 enzymes. An alternative approach to treating these brain tumors entails the exploitation, rather than inhibition, of IDH1 mutant enzymes through the discovery of associated synthetic lethal interactions. Our previous work describing nitrogen metabolism reprogramming by IDH1 mutations led to the development of a new synthetic lethality-based treatment strategy that is currently being tested in a Phase I trial for glioma patients (NCT03528642).

We are pursuing both hypothesis-driven and unbiased approaches to identify additional synthetic lethal interactions with the canonical IDH1 R132H oncogene. Because radiation is a cornerstone of the standard-of-care treatment protocol for glioma, we are particularly interested in discovering collateral vulnerabilities induced by IDH1 mutations that impact radiosensitivity. To evaluate the translational relevance of our findings, we use patient-derived and genetically engineered mouse models of glioma to conduct preclinical efficacy studies. Our long-term goal is to lay the basic and translational scientific groundwork needed to support clinical testing of new glioma treatment strategies using IDH1 mutations as predictive biomarkers.

About Dr. McBrayer

Sam McBrayer received his bachelor’s degree in biochemistry from Baylor University and went on to obtain his Ph.D. in cancer biology from Northwestern University’s Feinberg School of Medicine. At Northwestern, he worked to explain the molecular underpinnings of enhanced glucose transport activity in multiple myeloma in the laboratory of Dr. Steven Rosen. Dr. McBrayer then joined the laboratory of Dr. William G. Kaelin, Jr. at the Dana-Farber Cancer Institute and Harvard Medical School as an American Cancer Society Postdoctoral Fellow. During his time in the Kaelin Laboratory, he studied metabolic reprogramming in glioma and developed new strategies for brain tumor therapy.

In 2019, Dr. McBrayer joined the faculty of Children’s Medical Center Research Institute at UT Southwestern as an assistant professor in pediatrics. Since then, he has received awards from the National Cancer Institute and the Cancer Prevention and Research Institute of Texas.

Selected Publications

Koduri, V., McBrayer, S.K., Liberzon, E., Wang, A.C., Briggs, K.J., Cho, H., and Kaelin, W.G. (2019). Peptidic Degron for IMiD-Induced Degradation of Heterologous Proteins. PNAS 116, 2539-2544. (PubMed)

McBrayer, S.K., Mayers, J.R., DiNatale, G.J., Shi, D.D., Khanal, J., Chakraborty, A.A., Sarosiek, K.A., Briggs, K.J., Robbins, A.K., Sewastianik, T., Shareef, S.J., Olenchock, B.A., Parker, S.J., Tateishi, K., Spinelli, J.B., Islam, M., Haigis, M.C., Looper, R.E., Ligon, K.L., Bernstein, B.E., Carrasco, R.D., Cahill, D.P., Asara, J.M., Metallo, C.M., Yennawar, N.H., Vander-Heiden, M.G., and Kaelin, W.G. (2018). Transaminase Inhibition by 2-Hydroxyglutarate Impairs Glutamate Biosynthesis and Redox Homeostasis in Glioma. Cell 175, 101-116. (PubMed)

McBrayer, S.K., Olenchock, B.A., DiNatale, G.J., Shi, D.D., Khanal, J., Jennings, R.B., Novak, J.S., Oser, M.G., Robbins, A.K., Modiste, R., Bonal, D., Moslehi, J., Bronson, R.T., Neuberg, D., Nguyen, Q.D., Signoretti, S., Losman, J.A., and Kaelin, W.G. (2018). Autochthonous Tumors Driven by Rb1 Loss Have an Ongoing Requirement for the RBP2 Histone Demethylase. PNAS 115, E3741-E3748.  (PubMed)

McBrayer, S.K., Yarrington, M., Qian, J., Feng, G., Shanmugam, M., Gandhi, V., Krett, N.L., and Rosen, S.T. (2012). Integrative Gene Expression Profiling Reveals G6PD-mediated Resistance to RNA-directed Nucleoside Analogues in B Cell Neoplasms. PLOS One 7, e41455. (PubMed)

McBrayer, S.K., Cheng, J.C., Singhal, S., Krett, N.L., Rosen, S.T., and Shanmugam, M. (2012). Multiple Myeloma Exhibits Novel Dependence on GLUT4, GLUT8, and GLUT11: Implications for Glucose Transporter-directed Therapy. Blood 119, 4686-97. (PubMed)

Lab Members

Mike Levitt, M.S.

Research Technician

Min Xu, M.D., Ph.D.

Research Scientist