The PI-3 kinase-Akt-MDM2-survivin signaling axis in high-risk neuroblastoma: A target for PI-3 kinase inhibitor intervention

Susan K. Peirce, Harry W. Findley, Chengyu Prince, Anindya Dasgupta, Todd Cooper, Donald L. Durden

Research output: Contribution to journalArticlepeer-review

18 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)325-335
Number of pages11
JournalCancer Chemotherapy and Pharmacology
Volume68
Issue number2
DOIs
StatePublished - Aug 2011

Keywords

  • MDM2
  • Neuroblastoma
  • Pan PI3-kinase inhibitor
  • SF1126
  • Survivin

ASJC Scopus subject areas

  • Oncology
  • Toxicology
  • Pharmacology
  • Cancer Research
  • Pharmacology (medical)

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