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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Official URL: http://doi.org/10.1016/j.molonc.2015.11.005 |
Abstract
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 |
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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: | https://kar.kent.ac.uk/id/eprint/55391 (The current URI for this page, for reference purposes) |
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