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A Phase I/Ib Trial Targeting the Pi3k/Akt Pathway Using Perifosine: Long-term Progression-free Survival of Patients with Resistant Neuroblastoma

Overview
Journal Int J Cancer
Specialty Oncology
Date 2016 Sep 22
PMID 27649927
Citations 24
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Abstract

AKT plays a pivotal role in driving the malignant phenotype of many cancers, including high-risk neuroblastoma (HR-NB). AKT signaling, however, is active in normal tissues, raising concern about excessive toxicity from its suppression. The oral AKT inhibitor perifosine showed tolerable toxicity in adults and in our phase I trial in children with solid tumors (clinicaltrials.gov NCT00776867). We now report on the HR-NB experience. HR-NB patients received perifosine 50-75 mg m  day after a loading dose of 100-200 mg m on day 1, and continued on study until progressive disease. The 27 HR-NB patients included three treated for primary refractory disease and 24 with disease resistant to salvage therapy after 1-5 (median 2) relapses; only one had MYCN-amplified HR-NB. Pharmacokinetic studies showed μM concentrations consistent with cytotoxic levels in preclinical models. Nine patients (all MYCN-non-amplified) remained progression-free through 43+ to 74+ (median 54+) months from study entry, including the sole patient to show a complete response and eight patients who had persistence of abnormal I-metaiodobenzylguanidine skeletal uptake but never developed progressive disease. Toxicity was negligible in all 27 patients, even with the prolonged treatment (11-62 months, median 38) in the nine long-term progression-free survivors. The clinical findings (i) confirm the safety of therapeutic serum levels of an AKT inhibitor in children; (ii) support perifosine for MYCN-non-amplified HR-NB as monotherapy after completion of standard treatment or combined with other agents (based on preclinical studies) to maximize antitumor effects; and (iii) highlight the welcome possibility that refractory or relapsed MYCN-non-amplified HR-NB is potentially curable.

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References
1.
Guerreiro A, Boller D, Shalaby T, Grotzer M, Arcaro A . Protein kinase B modulates the sensitivity of human neuroblastoma cells to insulin-like growth factor receptor inhibition. Int J Cancer. 2006; 119(11):2527-38. DOI: 10.1002/ijc.22126. View

2.
Sartelet H, Imbriglio T, Nyalendo C, Haddad E, Annabi B, Duval M . CD133 expression is associated with poor outcome in neuroblastoma via chemoresistance mediated by the AKT pathway. Histopathology. 2012; 60(7):1144-55. DOI: 10.1111/j.1365-2559.2012.04191.x. View

3.
Li Z, Tan F, Liewehr D, Steinberg S, Thiele C . In vitro and in vivo inhibition of neuroblastoma tumor cell growth by AKT inhibitor perifosine. J Natl Cancer Inst. 2010; 102(11):758-70. PMC: 2879416. DOI: 10.1093/jnci/djq125. View

4.
Brodeur G, Pritchard J, Berthold F, Carlsen N, Castel V, Castelberry R . Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993; 11(8):1466-77. DOI: 10.1200/JCO.1993.11.8.1466. View

5.
Sun W, Modak S . Emerging treatment options for the treatment of neuroblastoma: potential role of perifosine. Onco Targets Ther. 2012; 5:21-9. PMC: 3299554. DOI: 10.2147/OTT.S14578. View