Oncotarget

Research Papers:

Combined mTOR and MEK inhibition is an effective therapy in a novel mouse model for angiosarcoma

Michelle L. Chadwick, Adam Lane, Dana Thomas, Amanda R. Smith, Angela R. White, Dominique Davidson, Yuxin Feng, Elisa Boscolo, Yi Zheng, Denise M. Adams, Anita Gupta, André Veillette and Lionel M.L. Chow _

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Oncotarget. 2018; 9:24750-24765. https://doi.org/10.18632/oncotarget.25345

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Abstract

Michelle L. Chadwick1,2, Adam Lane2, Dana Thomas2, Amanda R. Smith2, Angela R. White2, Dominique Davidson3, Yuxin Feng2, Elisa Boscolo2, Yi Zheng1,2, Denise M. Adams4, Anita Gupta5, André Veillette3 and Lionel M.L. Chow1,2

1Department of Cancer and Cell Biology, University of Cincinnati, Cincinnati, OH, USA

2Cancer and Blood Diseases Institute, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

3Institut de Recherches Cliniques de Montréal, Montréal, Canada

4Vascular Anomalies Center, Boston Children’s Hospital, Boston, MA, USA

5Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA

Correspondence to:

Lionel M.L. Chow, email: lionel.chow@cchmc.org

Keywords: angiosarcoma; mouse model; pre-clinical therapeutics; mTOR; MEK

Received: March 09, 2018     Accepted: April 21, 2018     Published: May 15, 2018

ABSTRACT

Angiosarcoma is an aggressive malignancy of vascular origin that occurs de novo or in the context of previous cancer therapy. Despite multi-modal aggressive treatment including surgical resection, chemotherapy, and radiation, five-year overall survival remains poor at 35%. Due to its rarity, little is known about its molecular pathology and clinical trials have been extremely difficult to conduct. Development of animal models for rare diseases like angiosarcoma is critical to improve our understanding of tumorigenesis and to test novel treatment regimens. A genetically engineered mouse model for angiosarcoma was generated by conditional deletion of Trp53, Pten, and Ptpn12 in endothelial cells. Tumors arising from these mice recapitulate the histology and molecular pathology of the human disease including hyperactivation of the PI3K/mTOR and MAPK signaling pathways. Treatment of tumor-bearing mice with mTOR or MEK inhibitors effectively inactivated signaling and resulted in reduced proliferation and elevated apoptosis leading to tumor regression. The effect of treatment on tumor growth was transient and proliferation was restored after a period of dormancy. However, combined inhibition of mTOR and MEK resulted in profound tumor regression which was sustained for the duration of treatment. These results suggest that angiosarcoma may be effectively treated by this drug combination.


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