Mechanism of Treatment Resistance in Human Glioblastoma

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.

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