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Emerging treatment options for the treatment of neuroblastoma: potential role of perifosine

Author(s): Sun W | Modak S

Journal: OncoTargets and Therapy
ISSN 1178-6930

Volume: 2012;
Issue: default;
Start page: 21;
Date: 2012;
Original page

Weili Sun1, Shakeel Modak21Department of Pediatrics, Keck School of Medicine, University of Southern California, Children's Hospital of Los Angeles, Los Angeles, CA, USA; 2Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, NY, USAAbstract: Achieving a cure for high-risk neuroblastoma, the most common extracranial solid tumor in children, remains a formidable task despite the recent addition of antibody-mediated anti-GD2 immunotherapy to established multimodality therapy. The PI3K/Akt pathway is a pivotal signaling pathway utilized by a plethora of receptor tyrosine kinases that contribute to the aggressive phenotype of high-risk neuroblastoma. Akt is aberrantly activated in high-risk neuroblastoma and is therefore an attractive therapeutic target. Perifosine is the best-characterized Akt inhibitor in preclinical studies and in clinical trials in adults, although safety in children is not yet confirmed. It is a synthetic third-generation alkylphospholipid with good oral bioavailability and modest side effects. Perifosine targets the lipid-binding PH domain of Akt and inhibits the translocation of Akt to the cell membrane, an essential step for Akt activation. It decreases Akt phosphorylation and increases caspase-dependent apoptosis in neuroblastoma cell lines, inhibits growth of neuroblastoma xenografts, and overcomes RTK/ligand-mediated chemoresistance. It is currently being studied in two Phase I clinical trials in children with recurrent or refractory solid tumors including neuroblastoma. In the single agent trial ( identifier NCT00776867), maximum tolerated dose has not yet been reached and pharmacokinetic data has been accrued. In the second study ( identifier NCT01049841), patients are treated with a combination of perifosine and the mTOR-inhibitor temsirolimus based on preclinical data showing synergy of the two agents, and the premise that direct Akt inhibition may overcome Akt activation secondary to mTOR inhibition. Based on results from adult trials, it is unlikely that perifosine alone will produce dramatic therapeutic effects against high-risk neuroblastoma. However, given the recent encouraging early-phase combination therapy results in adults with multiple myeloma and colorectal carcinoma, rational perifosine-containing combination regimens hold promise for neuroblastoma therapy. These will be explored after safety in children is established in Phase I studies.Keywords: neuroblastoma, Akt pathway, perifosine
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