Synthetically Lethal Nanoparticles for Treatment of Endometrial Cancer

Uterine serous carcinoma, one of the most aggressive types of endometrial cancer, is characterized by poor outcomes and mutations in the tumor suppressor p53. Our objective was to engender synthetic lethality to paclitaxel, the frontline treatment for endometrial cancer, in tumors with mutant p53 and enhance therapeutic efficacy using polymeric nanoparticles. First we identified the optimal nanoparticle formulation through comprehensive analyses of release profiles, cellular uptake and cell viability studies. Not only were paclitaxel-loaded nanoparticles superior to paclitaxel in solution, but the combination of paclitaxel-loaded nanoparticles with the antiangiogenic molecular inhibitor, BIBF-1120, promoted synthetic lethality specifically in cells with loss of function p53 mutation. In a xenograft model of endometrial cancer, this combinatorial therapy resulted in marked inhibition of tumor progression and extended survival. Together, our data provide compelling evidence for future studies of BIBF-1120- and paclitaxel-loaded nanoparticles as a therapeutic opportunity for loss of function p53 cancers.