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Synthetically lethal nanoparticles for treatment of endometrial cancer

2017; Nature Portfolio; Volume: 13; Issue: 1 Linguagem: Inglês

10.1038/s41565-017-0009-7

1748-3395

Kareem Ebeid, Xiangbing Meng, Kristina W. Thiel, Anh-Vu Do, Sean M. Geary, Angie S. Morris, Erica L. Pham, Amaraporn Wongrakpanich, Yashpal S. Chhonker, Daryl J. Murry, Kimberly K. Leslie, Aliasger K. Salem,

MicroRNA in disease regulation

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