Influence of DNA Repair on PARP Inhibitor Efficacy in Glioblastoma Multiforme
Investigators in the Mayo Clinic Brain Cancer SPORE are researching strategies to improve the efficacy of temozolomide for glioblastoma.
The addition of temozolomide during and after radiation therapy improves survival for patients with newly diagnosed glioblastoma multiforme and is the current standard of care. However, the survival benefit of temozolomide therapy is limited by the development of temozolomide resistance in almost all patients.
Because of that, the Mayo Clinic Brain Cancer SPORE has significant interest in identifying molecular sensitizing strategies to improve the efficacy of temozolomide.
The Brain Cancer SPORE is working on a strategy that targets the repair of temozolomide-induced DNA damage in inhibition of poly-ADP-ribose polymerase (PARP). PARP is indirectly involved in numerous repair pathways, and previous data suggest that PARP inhibitors will sensitize essentially all tumors to temozolomide.
The project's preliminary in vivo data in a panel of primary glioblastoma multiforme xenografts confirms a robust sensitizing effect of the PARP inhibitor ABT-888 when combined with temozolomide or temozolomide and radiation therapy. However, the data also demonstrate that combination therapy with PARP inhibitors is only effective in tumors that are inherently sensitive to temozolomide.
Defects in homologous recombination-mediated DNA repair are associated with increased sensitivity to temozolomide and to PARP inhibitor therapy.
The development of effective chemo- and radiosensitizing strategies could significantly improve the survival of patients with glioblastoma multiforme. PARP inhibitors show significant promise as a specific temozolomide-sensitizing strategy.
This Mayo Clinic Brain Cancer SPORE project is testing whether defects in DNA repair within tumors can be used to predict response to the combination of a PARP inhibitor with standard chemoradiotherapy in glioblastoma multiforme. Ultimately, this could lead to the use of molecular markers to customize therapy.
The research project on PARP inhibitor efficacy has three main aims.
Aim 1: Deregulation of homologous recombination
The Brain Cancer SPORE is testing whether deregulation of homologous recombination is associated with greater temozolomide-sensitizing effects of PARP inhibitors.
Defects in homologous recombination capacity are associated with increased efficacy of PARP inhibitors alone and in combination with cytotoxic chemotherapy. A subset of glioblastoma multiforme harbors mutations within genes important for homologous recombination activity.
This aim is testing whether molecular defects within these genes influence the efficacy of combined ABT-888/temozolomide therapy.
Aim 2: Influence of combination therapy on resistance emergence
The Brain Cancer SPORE is evaluating the influence of combination therapy on resistance emergence.
This project's preliminary data demonstrate a loss of efficacy of PARP inhibitors in models of acquired temozolomide resistance. These data suggest that emergence of temozolomide resistance may negatively impact the efficacy of combined therapy.
Conversely, other data suggest that radiation may influence the emergence of temozolomide resistance in some tumors.
This aim will use the project's xenograft models to characterize the interplay between temozolomide resistance and PARP inhibitor therapy.
Aim 3: ABT-888 combined with chemoradiotherapy
In this project, Mayo Clinic brain cancer researchers are evaluating whether a molecular signature can identify patients likely to benefit from ABT-888 combined with chemoradiotherapy.
PARP plays crucial roles in homologous recombination-mediated repair of O6MG-induced replication fork collapse. Because suppression of O-6-methylguanine-DNA methyltransferase (MGMT) by promoter methylation is permissive for replication arrest, this project hypothesizes that MGMT promoter methylation, potentially combined with other molecular features, can be used to enrich the cohort for patients likely to benefit from combined therapy.
The project team plans to test this in a single-arm phase II clinical trial.
Co-leaders of this Brain Cancer SPORE project are:
The co-investigator is: