KU-0059436 plus radiation as first line therapy for glioblastoma multiforme: rationale and phase I clinical trial protocol
Fiona Dungey1, Dana Loeser1, Anthony Chalmers2
1Genome Damage and Stability Centre, University of Sussex, Brighton, UK, 2Brighton and Sussex Medical School, Brighton, UK
Background
Glioblastoma multiforme (GBM) is the commonest and most aggressive primary brain tumour. Patients who tolerate surgery, radiotherapy and chemotherapy have a median survival of 15 months; poor performance status patients receive radiotherapy alone and survive for 4 – 6 months. Radiation dose is limited by the risk of permanent damage to normal brain. Since GBM are rapidly dividing whereas normal brain is predominantly post-mitotic, the therapeutic ratio may be enhanced by a replication-specific radiosensitising agent. KU-0059436 is an orally bioavailable chemical inhibitor of poly(ADP-ribose) polymerase (PARP) that is extremely well tolerated in vivo and has radiosensitising properties in vitro. Here we demonstrate that the radiosensitising effects of KU-0059436 are dependent on DNA replication and outline a phase I clinical trial of radiotherapy plus KU-0059436 in GBM.
Results
Clonogenic survival analysis of human glioma cells show that inhibition of DNA replication abrogates the radiosensitising effects of KU-0059436, whereas enrichment for S-phase cells enhances it. Radiosensitisation is enhanced when glioma cells are exposed to a fractionated regime. Assays of DNA damage and repair demonstrate a replication-dependent increase in radiation-induced double strand breaks.
Discussion
The replication dependence of the radiosensitising effect of KU-0059436 indicates that combining it with radiotherapy may enhance the therapeutic ratio for GBM. With the support of KuDOS Pharmaceuticals (AstraZeneca) and the UK National Cancer Research Institute Brain Tumour Group, a phase I clinical trial of KU-0059436 plus radiotherapy in patients with newly-diagnosed GBM has been developed; the protocol will be presented.
