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

Suzy Kim; Rebecca D Dodd; Jeffrey K Mito; Yan Ma; Yongbaek Kim; Richard F Riedel; David G Kirsch

doi:10.1155/2012/680708

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

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

Suzy Kim, Rebecca D Dodd, Jeffrey K Mito, Yan Ma, Yongbaek Kim, Richard F Riedel and David G Kirsch

Sarcoma, Vol.2012, 680708

2012

DOI: 10.1155/2012/680708

PMCID: PMC3350993

PMID: 22619567

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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 (n=15) 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 (n=10), which was also seen in combination with doxorubicin (n=10). Additionally, BKM120 treatment produced a robust delay in tumor growth kinetics. BEZ235-treated tumors (n=9) showed a complete response rate of 11.1%. Combining BEZ235 with doxorubicin (n=10) increased the complete response rate to 50% (P=0.035). These studies demonstrate that PI3K pathway inhibition is a viable and attractive target for soft-tissue sarcomas.

Details

Title: Subtitle: Efficacy of Phosphatidylinositol-3 Kinase Inhibitors in a Primary Mouse Model of Undifferentiated Pleomorphic Sarcoma
Creators: Suzy Kim - Duke University
Rebecca D Dodd - University of Iowa, Internal Medicine
Jeffrey K Mito - Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 91006, Durham, NC 27710, USA
Yan Ma - Department of Radiation Oncology, Duke University Medical Center, Box 91006, Durham, NC 27710, USA
Yongbaek Kim - Seoul National University
Richard F Riedel - Division of Medical Oncology, Duke University Medical Center, Box 91006, Durham, NC 27710, USA
David G Kirsch - Department of Radiation Oncology, Duke University Medical Center, Box 91006, Durham, NC 27710, USA, Department of Pharmacology and Cancer Biology, Duke University Medical Center, Box 91006, Durham, NC 27710, USA
Resource Type: Journal article
Publication Details: Sarcoma, Vol.2012, 680708
DOI: 10.1155/2012/680708
PMID: 22619567
PMCID: PMC3350993
NLM abbreviation: Sarcoma
ISSN: 1357-714X
eISSN: 1369-1643
Grant note: DOI: 10.13039/100000048, name: American Cancer Society, award: R01 CA138265
Language: English
Date published: 2012
Academic Unit: Hematology, Oncology, and Blood & Marrow Transplantation; Internal Medicine
Record Identifier: 9984094563102771

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