title: Efficacy of phosphatidylinositol-3 kinase inhibitors in a primary mouse model of undifferentiated pleomorphic sarcoma.
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.
authors.affiliation: Department of Radiation Oncology, Duke University Medical Center, Box 91006, Durham, NC 27710, USA.
authors.forename: Suzy
authors.initials: S
authors.lastname: Kim
authors.forename: Rebecca D
authors.initials: RD
authors.lastname: Dodd
authors.forename: Jeffrey K
authors.initials: JK
authors.lastname: Mito
authors.forename: Yan
authors.initials: Y
authors.lastname: Ma
authors.forename: Yongbaek
authors.initials: Y
authors.lastname: Kim
authors.forename: Richard F
authors.initials: RF
authors.lastname: Riedel
authors.forename: David G
authors.initials: DG
authors.lastname: Kirsch