Virginia Tech® home

Mechanism of Treatment Resistance in Human Glioblastoma

Timothy A. Johnson Medical Scholar Lecture presented by the Fralin Biomedical Research Institute at VTC and the Virginia Tech Carilion School of Medicine

Archived Lecture: Mechanism of Treatment Resistance in Human Glioblastoma

Date: April 16, 2021
Time: 1:00 p.m. - 2:00 p.m.

About this Lecture

The standard therapy for Glioblastoma (GBM), the most lethal primary brain tumor, has been surgical resection followed by chemoradiation and adjuvant temozolomide (TMZ). However, the survival of patients with GBM remains unacceptably low at 16-18 months, with little improvement over the last 20 years. This is due to a high level of resistance to therapy attributing to tumor heterogeneity, and intrinsic tumor cell resistance and tumor environment suppression. The cytotoxicity of TMZ is mediated by its addition of methyl groups at N7 and O6 sites on guanines and the O3 site on adenines in genomic DNA. In approximately 60% of patients, O6-methylguanine (O6-MetG) is rapidly removed by O6-methylguanine-DNA methyltransferase (MGMT), conferring resistance to TMZ chemotherapy.  Thus, inhibition of TMZ-induced DNA damage repair represents an attractive strategy for potentiating the activity of TMZ. Poly-ADP-ribose polymerase (PARP) is critical for regulating a variety of DNA damage repair mechanisms such as BER/SSBR, and PARP inhibitors have been shown to have single agent activity in breast and ovarian cancer patients with BRCA ½ mutations. Dr. Yung's lab has been studying the function of several PARP inhibitors. The lab first observed EGFR amplification is a marker of single agent activity with PARP/DNA complex trapping PARP inhibitors like Telazoparib, olaparib and pamiparib. Interestingly, the researchers also found that PARP binds to MGMT, and this binding is increased by TMZ treatment. The lab further observed that PARP binding leads to poly(ADP-ribosyl)ation (PARylation) of MGMT which is necessary for MGMT removal O6-methylguanine lesions in damaged DNA; and that PARP inhibitors reverse this action and inhibit MGMT removal of O6-MetG. Combination experiments of TMZ and PARP inhibitors showed increased DSB as shown by H2AX and 53P1 foci formation. Combination of TMZ and PARP inhibitor also significantly inhibited tumor growth and increase survival in animals. In summary, Yung and his lab have discovered a unique function of PARP inhibitor in reversing tumor resistance to TMZ chemotherapy in patients with MGMT unmethylated GBM: blocking BER/SSBR pathway to repair TMZ induced N7-Met and O3-MetA, and more importantly, suppressing MGMT activity to repair O6-MetG, resulting in augmented TMZ cytotoxicity. The lab also demonstrated EGFR amplification could serve as a biomarker for PARP inhibitor activity. Based on these data, Yung's lab is planning clinical trials to test the combination of TMZ and a brain penetrant PARP inhibitors in MGMT unmethylated GBM.

Additional Details 

This is a free event hosted by the Fralin Biomedical Research Institute and the Virginia Tech Carilion School of Medicine. The Timothy A. Johnson Medical Scholar Lecture Series hosts clinician scientists who are exploring frontiers of medicine. These lectures are principally intended for Virginia Tech Carilion School of Medicine students and Virginia Tech students in Translational Biology, Medicine, and Health graduate program. Virginia Tech and Carilion Clinic faculty, staff, and students may also attend.


You May Also Be Interested In...

  • Home Item
    In Person Seminar: Sustaining Power: Building Energy Networks in Striated Muscles , home

    Sept. 22, 2023, 11:00 a.m. | Brian Glancy, Ph.D., Senior Investigator, Muscle Energetics Laboratory, National Heart, Lung and Blood Institute, National Institutes of Health | Pioneers in Biomedical Research Seminar Series | Co-Sponsored by the Fralin Biomedical Research Institute Center for Exercise Medicine Research

  • Home Item
    Machine Learning and Human Thought - A Modern Frontier , home

    Sept. 28, 2023, 5:30 p.m. (Reception at 5 p.m.) | Read Montague, Ph.D., Virginia Tech Carilion Vernon Mountcastle Research Professor and Director, Center for Human Neuroscience Research, Fralin Biomedical Research Institute; Professor, Department of Physics, Virginia Tech College of Science | Maury Strauss Distinguished Public Lecture

  • Home Item
    In Person Seminar: Mitochondrial Ion Stress in Neurodegeneration , home

    Sept. 29, 2023, 11:00 a.m. | Xinnan Wang, M.D., Ph.D., Associate Professor, Neurosurgery, Stanford University School of Medicine | Co-Sponsored by the Fralin Biomedical Research Institute Center for Neurobiology Research

  • Home Item
    In Person Seminar: Precision Medicine in Cardiac Electrophysiology , home

    Oct. 6, 2023, 11:00 a.m. | Jennifer Silva, M.D., Professor of Pediatrics and Pediatric Cardiology, Director of Pediatric Electrophysiology, Washington University School of Medicine in St. Louis; Jonathan Silva, Ph.D., Professor, Biomedical Engineering and Computer Science and Engineering, Washington University in St. Louis; and | Co-Sponsored by the Fralin Biomedical Research Institute Center for Vascular and Heart Research

  • Home Item
    Cloudy with a Chance of Science: The Intersection of Wicked Problems, Perception, Communication, and Risk , home

    Oct. 19, 5:30 p.m. (Reception at 5 p.m.) | J. Marshall Shepherd, Ph.D., Georgia Athletic Association Distinguished Professor of Atmospheric Sciences and Geography, Director, UGA Atmospheric Sciences Program, University of Georgia, and Member, National Academy of Engineering, National Academy of Sciences, and American Academy of Arts and Sciences | Maury Strauss Distinguished Public Lecture

W.K. Alfred Yung, M.D., to present at Fralin Biomedical Research Institute

W.K.  Alfred Yung, M.D.

Professor, Department of Neuro-Oncology, Division of Cancer Medicine; Senior Advisor, Brain Tumor Center; Moonshot Executive Committee Member, The University of Texas MD Anderson Cancer Center