Dr Fashemi on the Effect of Entinostat on Olaparib Responsiveness in Mouse HRP Ovarian Cancer Models

Bisiayo Fashemi, PhD, post-doctoral research associate, Khabele Lab, Department of Obstetrics and Gynecology, Washington University School of Medicine, discusses how the addition of entinostat (SNDX-275) to olaparib (Lynparza) may help combat PARP inhibitor-resistance in homologous recombination proficient (HRP) ovarian cancer, as well as the clinical significance of utilizing mouse organoid models to investigate such strategies. 

The addition of the epigenetic drug, entinostat, to olaparib treatment was evaluated in a mouse model of ovarian cancer. The combination regimen was hypothesized to re-sensitize PARP inhibitor-resistant ovarian cancer cells, thereby improving patient responses.

Results from the study showed that therapy with entinostat and olaparib significantly reduced cell proliferation in HRP and induced olaparib-resistant ID8 cells when compared with olaparib alone, Fashemi states. The combination regimen was also associated with increased damage to DNA in tumor cells, and decreased RAD51 PARP inhibitor-resistant cells. Furthermore, the size of ovarian cancer organoids were greatly reduced with entinostat and olaparib vs the control, Fashemi adds.

These findings not only indicate that pretreatment with entinostat is an effective PARP re-sensitization strategy for both intrinsic and acquired olaparib-resistant ovarian cancer, but demonstrated the clinical utility of mouse-derived organoids for research in this disease space, Fashemi continues. These 3-D cultures can be sustained for long periods of time and are easily characterized. Moreover, they can recapitulate the tumor microenvironment and produce expected responses to both platinum chemotherapy and PARP inhibitor–based treatment, Fashemi emphasizes.

This research will be followed by an in vivo study of the combination in ovarian cancer organoids. Future research efforts should continue using both 2D-adherent and 3D organoid models to improve in vitro experiments, and investigate potential biomarkers of olaparib and entinostat combination therapy in ovarian cancer, Fashemi concludes.