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

Weili Sun, Shakeel Modak, Weili Sun, Shakeel Modak

Abstract

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 (ClinicalTrials.gov identifier NCT00776867), maximum tolerated dose has not yet been reached and pharmacokinetic data has been accrued. In the second study (ClinicalTrials.gov 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: Akt pathway; neuroblastoma; perifosine.

Figures

Figure 1
Figure 1
Diagrammatic representation of the Akt signaling pathway. Notes: Activation of receptor tyrosine kinase (RTK) by growth factor binding activates PIK3. Activated PI3K phosphorylates PIP2 and generates PIP3, a reaction that can be reversed by PTEN. The PH domain of Akt binds to PIP3, which then triggers a conformational change of Akt that results in the phosphorylation of two critical amino acids, Thr308 and Ser473 by PDK-1 and TORC2 respectively. The phosphorylated Akt then dissociates from the plasma membrane and targets downstream pathways including cell growth, survival, proliferation, and metabolism. Besides PTEN, this pathway is also negatively regulated by PHLPP, a protein serine/threonine phosphatase that can dephosphorylate Ser473 of Akt. Abbreviations: PIP2, Phosphatidylinositol (4,5)-bisphosphate; PIP3, Phosphatidylinositol (3,4,5)-trisphosphate; PDK1, 3-Phosphoinositide-dependent protein kinase 1; TORC2, mammalian target of rapamycin complex 2; PTEN, Phosphatase and tensin homolog; PHLPP, PH domain and Leucine rich repeat protein phosphatases; mTOR, mammalian target of rapamycin Bad, Bcl-xL/Bcl-2-associated death promoter; FKHR, Forkhead transcription factors; MDM2, mouse double minute 2; GSK3, glycogen synthase kinase 3.

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