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Novel pharmacodynamic biomarkers for MYCN protein and PI3K/AKT/mTOR pathway signaling in children with neuroblastoma

Smith, Jennifer R., Moreno, Lucas, Heaton, Simon P., Chesler, Louis, Pearson, Andrew D.J., Garrett, Michelle D. (2016) Novel pharmacodynamic biomarkers for MYCN protein and PI3K/AKT/mTOR pathway signaling in children with neuroblastoma. Molecular Oncology, 10 (4). pp. 538-552. ISSN 1574-7891. (doi:10.1016/j.molonc.2015.11.005) (KAR id:55391)

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There is an urgent need for improved therapies for children with high-risk neuroblastoma

where survival rates remain low. MYCN amplification is the most common genomic change

associated with aggressive neuroblastoma and drugs targeting PI3K/AKT/mTOR, to activate

MYCNoncoprotein degradation, are entering clinical evaluation. Our aim was to develop and

validate pharmacodynamic (PD) biomarkers to evaluate both proof of mechanism and proof

of concept for drugs that block PI3K/AKT/mTOR pathway activity in children with neuroblastoma.

Wehave addressed the issue of limited access to tumor biopsies for quantitative detection

of protein biomarkers by optimizing a three-color fluorescence activated cell sorting

(FACS) method to purify CD45?/GD2+/CD56+ neuroblastoma cells from bone marrow. We

then developed a novel quantitative measurement of MYCN protein in these isolated neuroblastoma

cells, providing the potential to demonstrate proof of concept for drugs that inhibit

PI3K/AKT/mTOR signaling in this disease. In addition we have established quantitative

detection of three biomarkers for AKT pathway activity (phosphorylated and total AKT,

GSK3b and P70S6K) in surrogate platelet-rich plasma (PRP) frompediatric patients. Together

ournewapproachto neuroblastomacell isolation for protein detection and suite ofPD assays

provides for the first time the opportunity for robust, quantitative measurement of proteinbased

PD biomarkers in this pediatric patient population. These will be ideal tools to support

clinical evaluation of PI3K/AKT/mTOR pathway drugs and their ability to target MYCN oncoprotein

in upcoming clinical trials in neuroblastoma.

Item Type: Article
DOI/Identification number: 10.1016/j.molonc.2015.11.005
Uncontrolled keywords: Neuroblastoma; MYCN; AKT; Pharmacodynamic; Biomarker
Subjects: Q Science
Divisions: Divisions > Division of Natural Sciences > Biosciences
Depositing User: Michelle Garrett
Date Deposited: 11 May 2016 15:02 UTC
Last Modified: 08 Dec 2022 22:38 UTC
Resource URI: (The current URI for this page, for reference purposes)
Garrett, Michelle D.:
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