Increasing the therapeutic index of radiation by combination with rucaparib in cervical cancer

Cervical cancer is the 4th most common cancer in women worldwide. Despite vaccination, developing countries in the Sub-Saharan Africa and South-Eastern Asia are mostly affected. In the UK, the peak age of incidence is 25-30 years with a 10-year survival rate 63%. For the locally advanced disease common treatment regimen is cisplatin ± radiotherapy. However, cisplatin induced kidney toxicity results in discontinuation of the treatment and therapy failure. The stage IVA disease is inoperable due to large tumour volume and candidates for curative radiotherapy only. Further, within these giant tumours poor availability of oxygen in blood flow results hypoxia induced radioresistance. New therapeutic strategy is therefore urgently needed. Previous studies have shown that the PARP inhibitors (PARPi): RucaparibTM, OlaparibTM, nicotinamide and benzamides may increase tumour blood-flow and improve tumour oxygenation. Cisplatin-induced kidney toxicity is thought to be PARP-mediated with PARPi may potentially protect the kidneys. To provide pre-clinical data to justify a clinical trial the objectives of my project are to study: (1) the chemo-radiosensitising ability of RucaparibTM and (2) the ameliorating effect of RucaparibTM on cisplatin-induced kidney toxicity. If successful, this study will contribute new chemo-radiotherapeutic strategies to reduce cisplatin and (or) radiation doses in advanced stages of cervical cancer.