Abstract 570P
Background
Poly (ADP-Ribose) polymerase inhibitors (PARPi’s) are currently used for first and second line maintenance therapy of ovarian cancer (OC) in patients whose tumors harbor defects in homologous recombination. Unfortunately, the rapid emergence of resistance leads to a short duration of response, and thus preventing PARPi resistance and extending the spectrum of patients who would benefit from PARP inhibition are urgent needs. While multiple drug classes have demonstrated synergy when combined with PARPi’s preclinically, head-to-head comparisons which would facilitate clinical prioritization of the most promising combinations are missing. Here, we compare niraparib, an approved PARPi, in combination with various epigenetic regulators in OC cells to directly compare their combinatorial effects.
Methods
Using 38 molecularly characterized ovarian cell lines, we generated single agent proliferation data on all approved PARPi’s. We then took a subset of 10 cell lines and tested combinations of niraparib and a histone deacetylase inhibitor (SNDX-275), a hypomethylating agent (5-aza-2’deoxycytidine) and a bromodomain inhibitor (GSK525762). For all assays, cultured cells were seeded in 48 well plates, treated at varying doses and counted using an image based reader on day 7. Combination Index (CI) values were generated for combinations treatments, with values < 1.0 indicating synergistic, > 1.0 antagonistic and = 1.0 additive interactions.
Results
Significant synergistic inhibition was observed in OC cells treated with a combination of niraparib and 5-aza-2’deoxycytidine. All 10 cell lines responded synergysitcally to the combination with mean CI values ranging from 0.29 [P < 0.05] to 0.35 [P < 0.05] at clinically relevant doses. In contrast, combinations with SNDX-275 and GSK525762, demonstrated less pronounced combinatorial responses. Detailed mean CI values will be reported as well as RNAseq data on the effects of each epigenetic drug across all 10 OC lines.
Conclusions
Consistent synergistic interactions of niraparib plus 5-aza-2’deoxycytidine across a wide range of clinically relevant concentrations in ovarian cancer cells indicate that it is a rational combination to test and prioritize in human clinical trials.
Clinical trial identification
Editorial acknowledgement
Legal entity responsible for the study
Gottfried E. Konecny MD, UCLA Translational Oncology Research Laboratory.
Funding
UCLA Translational Oncology Research Laboratory.
Disclosure
M.S. McDermott: Financial Interests, Personal and Institutional, Stocks/Shares, Co-founder: 1200 Pharma LLC, TORL Biotherapeutics. G.E. Konecny: Financial Interests, Personal and Institutional, Speaker’s Bureau: GSK. All other authors have declared no conflicts of interest.