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Synthetically lethal nanoparticles for treatment of endometrial cancer

Nature Nanotechnology volume 13, pages 72–81 (2018)Cite this article

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Abstract

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.

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Fig. 1: Concomitant treatment of PTXs + BIBFs significantly inhibited cell growth only in EC cells with LOF p53 mutation.
Fig. 2: PTXp was successfully prepared and microscopically characterized.
Fig. 3: PTXp (75/T) exhibited the highest cell killing and uptake with Hec50co cells, in addition to a slower drug release.
Fig. 4: Combining BIBFs with PTXp (75/T) induced synthetic lethality in LOF p53 cells through the abrogation of the G2/M checkpoint.
Fig. 5: The combination of PTXp (75/T) + BIBFp (75/T) demonstrated the highest reduction in tumour progression, extended median survival and had favourable safety in vivo.

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Acknowledgements

This work was supported by the National Cancer Institute at the National Institutes of Health (P50 CA97274/UI Mayo Clinic Lymphoma SPORE grant to A.K.S., P30 CA086862 Cancer Center support grant to A.K.S., R01 CA099908 to K.K.L. and R01 CA184101 to X.M. and K.K.L.), the Lyle and Sharon Bighley Professorship (A.K.S.) and the Department of Obstetrics and Gynecology Research Fund (K.K.L.). K.E. acknowledges the Egyptian Ministry of Higher Education for a graduate fellowship award. We acknowledge the University of Iowa Central Microscopy Research Facility staff and especially K. Walters for her help with the histological analysis data. The flow cytometry data were obtained at the Flow Cytometry Facility, which is a Carver College of Medicine/Holden Comprehensive Cancer Center core research facility at the University of Iowa.

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Authors and Affiliations

  1. Division of Pharmaceutics and Translational Therapeutics, College of Pharmacy, University of Iowa, Iowa City, IA, USA

    Kareem Ebeid, Anh-Vu Do, Sean M. Geary, Angie S. Morris, Erica L. Pham, Amaraporn Wongrakpanich, Daryl J. Murry & Aliasger K. Salem

  2. Department of Obstetrics and Gynecology, University of Iowa, Iowa City, IA, USA

    Xiangbing Meng, Kristina W. Thiel & Kimberly K. Leslie

  3. Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA, USA

    Xiangbing Meng, Kimberly K. Leslie & Aliasger K. Salem

  4. Department of Pharmacy, Faculty of Pharmacy, Mahidol University, Bangkok, Thailand

    Amaraporn Wongrakpanich

  5. Department of Pharmacy Practice, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE, USA

    Yashpal S. Chhonker & Daryl J. Murry

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Contributions

K.E., X.M., K.K.L. and A.K.S. conceived and designed the experiments. K.E., X.M., S.M.G., A.D., A.S.M., E.L.P., A.W., Y.S.C. and D.J.M. performed the experiments. K.E., K.W.T., K.K.L. and A.K.S. wrote and revised the manuscript.

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Correspondence to Kimberly K. Leslie or Aliasger K. Salem.

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K.W.T. is a co-founder of Immortagen Inc. All the other authors declare no competing financial interests.

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Ebeid, K., Meng, X., Thiel, K.W. et al. Synthetically lethal nanoparticles for treatment of endometrial cancer. Nature Nanotech 13, 72–81 (2018). https://doi.org/10.1038/s41565-017-0009-7

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