Background: Glioblastoma is the most lethal human brain tumour. Standard-of-care treatment involves surgical resection followed by radiation therapy (RT) with concomitant and adjuvant temozolomide (TMZ). However, this approach is not curative, and glioblastoma cells can resist radiation-induced and TMZ-induced DNA damage. Therefore, survival outcomes remain dismal, with patients typically surviving up to 15 months post-diagnosis. There is an urgent need for improved therapies.
Methods: Cell cycle checkpoint inhibitors have been shown to enhance the genotoxic effects of radiation and chemotherapy. Patient-derived glioblastoma cells and established cell lines were used to explore whether an inhibitor of cell cycle checkpoint kinases 1/2 (LY2606368) could sensitise glioblastoma to conventional therapies. Glioblastoma cells were treated with radiation, TMZ or gemcitabine, another clinically-used chemotherapeutic, in combination with LY2606368 and drug interaction and clonogenicity assays were performed. Orthotopic xenograft mouse models were used to examine the molecular effects of treatment, and to assess any survival benefit of combining LY2606368 with RT or chemotherapy.
Results: In vitro, LY2606368 interacted synergistically with gemcitabine, but not with TMZ, in U87 and T98G glioblastoma cells. Clonogenicity assays using patient-derived glioblastoma cells demonstrated that LY2606368 enhanced RT-induced cell death. In vivo, immunohistochemistry revealed significant reductions in tumour cell proliferation when LY2606368 was combined with RT and gemcitabine. Furthermore, LY2606368 enhanced gemcitabine-induced DNA damage. Most importantly, co-administration of LY2606368 with either gemcitabine or TMZ significantly extended survival of mice with orthotopic glioblastoma.
Conclusions: Over the last decade no new drug has successfully improved the 5-year survival rate for glioblastoma in clinical trials. Using multiple mouse models, our data show that LY2606368 can sensitise glioblastoma cells to conventional chemotherapies, suggesting this drug has the potential to improve patient outcomes. Current studies will determine if similar survival benefits are achieved by combining LY2606368 with RT and these results will enable the rational design of a future clinical trial for glioblastoma patients.