Author(s): Peirce SK, Findley HW, Prince C, Dasgupta A, Cooper T, , Peirce SK, Findley HW, Prince C, Dasgupta A, Cooper T,
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Abstract 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.
This article was published in Cancer Chemother Pharmacol
and referenced in Journal of Cancer Science & Therapy