Combination therapy with decitabine and olaparib in poly(ADP-ribose) polymerase inhibitor (PARPi) resistant high grade serous ovarian cancer

Background: Recurrent high grade serous ovarian cancer (HGSOC) is incurable and lethal. Therefore, novel drug combinations are critically needed for this patient population. DNA methyltransferase inhibitors (DNMTi) can cause damage, which activates poly(ADP-ribose) polymerase (PARP) leads to PARP trapping. Additionally, DNMTi incorporated into replicating DNA, causes DNMT-DNA adducts that then degraded. the combination of decitabine inhibitor (PARPi) olaparib were tested in preclinical HGSOC models. Materials methods: RNA sequencing was performed on 300 samples determine versus low expression methyltransferases (DNMTs). Twenty-nine selected ex vivo 3D culture testing with titrating concentrations PARPi olaparib. In preparation studies, maximum tolerated dose determined. Results: demonstrated varying DNMT1, DNMT3A, DNMT3B. culture, about 10% (3/29) models a synergistic effect Of these three, one known be resistant animal thus patient-derived xenograft (PDX) studies. Prior pursuing PDX performed, female SCID-bg mice less than 20% weight loss overall good health condition scores. Conclusions: Synergy observed subset tumors by testing. Importantly, has activity PARPi-resistant, BRCA wildtype, homologous recombination proficient tumor, represents genotypic phenotypic characteristics most HGSOCs. This also well-tolerated SCID mice. No conflict interest.