TY - JOUR
T1 - The PI-3 kinase-Akt-MDM2-survivin signaling axis in high-risk neuroblastoma
T2 - A target for PI-3 kinase inhibitor intervention
AU - Peirce, Susan K.
AU - Findley, Harry W.
AU - Prince, Chengyu
AU - Dasgupta, Anindya
AU - Cooper, Todd
AU - Durden, Donald L.
N1 - Funding Information:
Acknowledgments We thank C. P. Reynolds for his kind gift of NB cells. We would like to thank N. Dey and Adam Marcus for technical assistance with confocal imaging. This work was supported by NIH-CA94233 (DLD), Alex’s Lemonade Stand Foundation (DLD), Magic Waters Foundation (DLD) and CURE Childhood Cancer (DLD and HWF).
PY - 2011/8
Y1 - 2011/8
N2 - Purpose: Studies of SF1126, an RGDS targeted, water-soluble prodrug of LY294002, are currently nearing completion in two adult Phase I trials. Herein, we performed a preclinical evaluation of SF1126 as a PI-3K inhibitor for Phase I trials in the treatment of recurrent neuroblastoma (NB). Methods: The effects of SF1126 on pAkt-MDM2 cell signaling, proliferation, apoptosis, and migration were determined using a panel of NB cell lines, and anti-tumor activity was determined using a xenograft model of NB. Results: SF1126 blocks MDM2 activation, IGF-1 induced activation of Akt, and the upregulation of survivin induced by IGF-1. It also increases sensitivity to doxorubicin in vitro and was found to exhibit marked synergistic activity in combination with doxorubicin. Treatment disrupts the integrin αvβ3/αvβ5-mediated organization of the actin cytoskeleton as well as the α4β1/ α5β1-mediated processes essential to metastasis. In vivo, SF1126 markedly inhibits tumor growth in NB xenografted mice (P < 0.05). Conclusions: A pan PI-3 kinase inhibitor has potent antitumor activity and induces apoptosis in multiple neuroblastoma cell lines. The observed effects of SF1126 on the p-Akt-MDM2-survivin axis suggest a patient selection paradigm in which NB tumors with increased pAkt-MDM2-survivin signaling may predict response to SF1126 alone or in combination with standard chemotherapy regimens that contain anthracyclines.
AB - Purpose: Studies of SF1126, an RGDS targeted, water-soluble prodrug of LY294002, are currently nearing completion in two adult Phase I trials. Herein, we performed a preclinical evaluation of SF1126 as a PI-3K inhibitor for Phase I trials in the treatment of recurrent neuroblastoma (NB). Methods: The effects of SF1126 on pAkt-MDM2 cell signaling, proliferation, apoptosis, and migration were determined using a panel of NB cell lines, and anti-tumor activity was determined using a xenograft model of NB. Results: SF1126 blocks MDM2 activation, IGF-1 induced activation of Akt, and the upregulation of survivin induced by IGF-1. It also increases sensitivity to doxorubicin in vitro and was found to exhibit marked synergistic activity in combination with doxorubicin. Treatment disrupts the integrin αvβ3/αvβ5-mediated organization of the actin cytoskeleton as well as the α4β1/ α5β1-mediated processes essential to metastasis. In vivo, SF1126 markedly inhibits tumor growth in NB xenografted mice (P < 0.05). Conclusions: A pan PI-3 kinase inhibitor has potent antitumor activity and induces apoptosis in multiple neuroblastoma cell lines. The observed effects of SF1126 on the p-Akt-MDM2-survivin axis suggest a patient selection paradigm in which NB tumors with increased pAkt-MDM2-survivin signaling may predict response to SF1126 alone or in combination with standard chemotherapy regimens that contain anthracyclines.
KW - MDM2
KW - Neuroblastoma
KW - Pan PI3-kinase inhibitor
KW - SF1126
KW - Survivin
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U2 - 10.1007/s00280-010-1486-7
DO - 10.1007/s00280-010-1486-7
M3 - Article
C2 - 20972874
AN - SCOPUS:79960924027
SN - 0344-5704
VL - 68
SP - 325
EP - 335
JO - Cancer Chemotherapy and Pharmacology
JF - Cancer Chemotherapy and Pharmacology
IS - 2
ER -