Pre-clinical imaging evaluation of the PARP inhibitor rucaparib

Abstract

Poly(ADP-ribose) polymerase 1 (PARP1) is a DNA-binding enzyme involved in DNA repair by the base-excision pathway. The inhibition of PARP1 is being investigated as a cancer treatment. Rucaparib (CO338) is a potent PARP 31 inhibitor currently in Phase II clinical development. In this thesis P in vivo MR Spectroscopy (MRS) and Dynamic Contrast Enhanced (DCE) MRI were used to study acute effects of rucaparib on energy metabolism and tumour vasculature. 1 31 18 18 Ex vivo H and P-MRS, and in vivo [ F]FLT and [ F]FDG-PET, were used to study effects of treatment with rucaparib on tumour metabolism and proliferation. A2780 and SW620 tumours implanted in mice were scanned in a horizontal Varian 7T MR system. Two i.v. injections of the MRI contrast agent gadoteridol were given 90 minutes apart with dynamic phosphorus MRS acquired following the injection of rucaparib, temozolomide or both drugs in combination. The 18 18 same tumours were evaluated by [ F]FLT- and [ F]FDG-PET after 5 daily treatments with rucaparib, temozolomide or the combination, and the livers of PARP1 knock out (KO) and wild type (WT) mice treated in a similar manner 1 31 were analysed by ex vivo H and P-MRS. Tumour uptake of gadoteridol changed significantly after treatment with hydralazine and higher doses of rucaparib in SW620 tumours, and following 31 hydralazine and 1mg/Kg of rucaparib in A2780 tumours. P-MRS studies revealed an increase in the inorganic phosphate (Pi) to β-NTP ratio, consistent with impairment of tumour energy metabolism following hydralazine treatment. 18 [ F]FLT-PET demonstrated a significant reduction in the SUV values in the 18 rucaparib/temozolomide combination group in SW620 tumours, and [ F]FDG- PET revealed a non-significant reduction in tumour metabolism in A2780 1 tumours. H ex vivo MRS demonstrated an increase in the liver NAD concentrations after treatment with rucaparib, but a decrease following the treatment with temozolomide, regardless of the PARP1 status. Together, these pre-clinical imaging studies have shown that MR can be used 18 to investigate the acute anti-vascular effects of rucaparib, that [ F]FLT-PET predicted subsequent changes in tumour volume following combined rucaparib 1 and temozolomide treatment, and that ex vivo H-MRS can be used in mechanistic studies of PARP inhibition. Both MRI/MRS and PET are potential pharmacodynamic and surrogate response imaging biomarkers for PARP inhibitors.