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Obstetrics and Gynecology International
Volume 2013 (2013), Article ID 828165, 10 pages
http://dx.doi.org/10.1155/2013/828165
Research Article

Strategies for Molecularly Enhanced Chemotherapy to Achieve Synthetic Lethality in Endometrial Tumors with Mutant p53

1Department of Obstetrics and Gynecology, University of Iowa Hospitals and Clinics, Iowa City, IA 52242, USA
2Holden Comprehensive Cancer Center, University of Iowa, Iowa City, IA 52242, USA
3Gillette Center for Gynecological Oncology, Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA

Received 31 May 2013; Accepted 10 October 2013

Academic Editor: Andrew P. Bradford

Copyright © 2013 Xiangbing Meng et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Serous uterine endometrial carcinomas are aggressive type II cancers with poor outcomes for which new treatment strategies are urgently needed, in particular, strategies that augment sensitivity to established chemotherapy regimens. The tumor suppressor gene TP53 is dysregulated in more than 90% of serous tumors, altering master regulators of the G2/M cell cycle checkpoint in unique and predictable ways and desensitizing cells to chemotherapy. We hypothesized that synthetic lethality can be achieved in endometrial cancer cells with mutant p53 by combining paclitaxel with agents to overcome G2/M arrest and induce mitotic catastrophe. The combination of BIBF1120, an investigational VEGFR, PDGFR, and FGFR multityrosine kinase inhibitor with established anti-angiogenic activity, with paclitaxel abrogated the G2/M checkpoint in p53-null endometrial cancer cells via modulation of G2/M checkpoint regulators followed by induction of mitotic cell death. In endometrial cancer cells harboring an oncogenic gain-of-function p53 mutation, synthetic lethality was created by combining paclitaxel with BIBF1120 and a histone deacetylase inhibitor, which serves to destabilize mutant p53. These cells were also sensitive to an inhibitor of the G2/M kinase Wee1 in combination with paclitaxel. These findings reveal that, in addition to antiangiogenic activity, the angiokinase inhibitor BIBF1120 can be used to restore sensitivity to paclitaxel and induce mitotic cell death in endometrial cancer cells with non-functional p53. These preclinical data serve as a critical platform for the creative design of future clinical trials utilizing molecularly enhanced chemotherapy to achieve synthetic lethality based on the mutational landscape.