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Sarcoma
Volume 2012, Article ID 680708, 8 pages
http://dx.doi.org/10.1155/2012/680708
Research Article

Efficacy of Phosphatidylinositol-3 Kinase Inhibitors in a Primary Mouse Model of Undifferentiated Pleomorphic Sarcoma

1Department of Radiation Oncology, Duke University Medical Center, Box 91006, Durham, NC 27710, USA
2Department of Radiation Oncology, Boramae Hospital, Seoul National University Hospital, Seoul 156-707, Republic of Korea
3Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 91006, Durham, NC 27710, USA
4Department of Clinical Pathology, College of Veterinary Medicine, Seoul National University, Seoul 156-707, Republic of Korea
5Division of Medical Oncology, Duke University Medical Center, Box 91006, Durham, NC 27710, USA

Received 4 January 2012; Revised 10 February 2012; Accepted 13 February 2012

Academic Editor: Luca Sangiorgi

Copyright © 2012 Suzy Kim 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

Recent advances in sarcoma genomics have identified novel mutations in the PI3K pathway in human sarcomas. Here, we use a mouse model of primary soft-tissue sarcoma for preclinical testing of doxorubicin and inhibitors of the PI3K pathway: BKM120 (PI3K inhibitor) and BEZ235 (a dual PI3K/mTOR inhibitor). Doxorubicin-treated tumors ( ) showed a partial response rate of 6.6%, just as the majority of human sarcomas do not respond to doxorubicin. Treatment with BKM120 elicited a partial response in 50% of tumors ( ), which was also seen in combination with doxorubicin ( ). Additionally, BKM120 treatment produced a robust delay in tumor growth kinetics. BEZ235-treated tumors ( ) showed a complete response rate of 11.1%. Combining BEZ235 with doxorubicin ( ) increased the complete response rate to 50% ( ). These studies demonstrate that PI3K pathway inhibition is a viable and attractive target for soft-tissue sarcomas.