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

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.

• Authors: Susan K Peirce, Harry W Findley, Chengyu Prince, Anindya Dasgupta, Todd Cooper, Donald L Durden
• Journal: Cancer chemotherapy and pharmacology (Cancer Chemother Pharmacol) Vol. 68 Issue 2 Pg. 325-35 (Aug 2011) ISSN: 1432-0843 [Electronic] Germany
• PMID: 20972874 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• BIRC5 protein, human
• Chromones
• Enzyme Inhibitors
• Inhibitor of Apoptosis Proteins
• Oligopeptides
• Phosphoinositide-3 Kinase Inhibitors
• Prodrugs
• SF 1126
• Survivin
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• Proto-Oncogene Proteins c-akt

Topics

• Animals
• Antineoplastic Agents (antagonists & inhibitors, pharmacology, therapeutic use)
• Apoptosis (drug effects)
• Cell Line, Tumor
• Cell Movement (drug effects)
• Cell Proliferation (drug effects)
• Chromones (antagonists & inhibitors, pharmacology, therapeutic use)
• Enzyme Inhibitors (pharmacology, therapeutic use)
• Female
• Humans
• Inhibitor of Apoptosis Proteins (metabolism)
• Mice
• Mice, Nude
• Neuroblastoma (drug therapy, metabolism, ultrastructure)
• Oligopeptides (antagonists & inhibitors, pharmacology, therapeutic use)
• Phosphoinositide-3 Kinase Inhibitors
• Phosphorylation (drug effects)
• Prodrugs (pharmacology, therapeutic use)
• Protein Processing, Post-Translational (drug effects)
• Proto-Oncogene Proteins c-akt (metabolism)
• Proto-Oncogene Proteins c-mdm2 (metabolism)
• Random Allocation
• Signal Transduction (drug effects)
• Survivin
• Tumor Burden (drug effects)
• Xenograft Model Antitumor Assays