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Prediction of neuroblastoma cell response to treatment with natural or synthetic retinoids using selected protein biomarkers.

ABSTRACT: Although the administration of retinoids represents an important part of treatment for children suffering from high-risk neuroblastomas, approximately 50% of these patients do not respond to this therapy or develop resistance to retinoids during treatment. Our study focused on the comparative analysis of the expression of five genes and corresponding proteins (DDX39A, HMGA1, HMGA2, HOXC9 and PBX1) that have recently been discussed as possible predictive biomarkers of clinical response to retinoid differentiation therapy. Expression of these five candidate biomarkers was evaluated at both the mRNA and protein level in the same subset of 8 neuroblastoma cell lines after treatment with natural or synthetic retinoids. We found that the cell lines that were HMGA2-positive and/or HOXC9-negative have a reduced sensitivity to retinoids. Furthermore, the experiments revealed that the retinoid-sensitive cell lines showed a uniform pattern of change after treatment with both natural and sensitive retinoids: increased DDX39A and decreased PBX1 protein levels. Our results showed that in NBL cells, these putative protein biomarkers are associated with sensitivity or resistance to retinoids, and their endogenous or induced expression can distinguish between these two phenotypes.

SUBMITTER: Dobrotkova V

PROVIDER: S-EPMC6561640 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Background: Neoadjuvant chemotherapy is increasingly being used to preoperatively shrink breast tumours prior to surgery. This approach also provides the opportunity to study the molecular changes associated with treatment and evaluate whether on-treatment sequential samples can improve response and outcome predictions over diagnostic or excision samples alone. Methods: A total of 95 samples from a cohort of 50 neoadjuvant chemotherapy-treated primary breast cancer patients (aged 29-76, 48% ER+, 20% HER2+) enrolled in the NEO trial taken before, at 2 weeks on-treatment, mid-therapy and at resection were sequenced with Ion Ampliseq transcriptome yielding expression values for 12,635 genes. Differential expression analysis was performed across 16 responders and 34 non-responders defined by pathological complete response and over treatment time to identify significantly differentially expressed genes, pathways and markers indicative of response status. Prediction accuracy was compared with estimations of established gene signatures, for this dataset and validated using data from the I-SPY1 trial. Results: AAGAB was identified as a novel on-treatment biomarker for pathological complete response, with an accuracy of 100% in the NEO training dataset and 78% accuracy in the I-SPY1 Trial. AAGAB levels on treatment were also significantly predictive of term survival (p = 0.048, p = 0.031) in the two cohorts. This single gene on-treatment biomarker, had greater predictive accuracy than established prognostic tests, Mammaprint and Pam50 risk of recurrence score, although interesting both of these tests performed better in the on-treatment rather than the accepted pre-treatment setting (accuracy improving consistently by 2-8%). Conclusion: Changes in gene expression measured in sequential samples from breast cancer patients receiving neoadjuvant chemotherapy resulted in the identification of a novel on-treatment biomarker and suggest that established prognostic tests may have greater prediction accuracy on- than before treatment. These results support the potential use and further evaluation of on- treatment testing in breast cancer to improve the accuracy of tumour response prediction.

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Prediction of neuroblastoma cell response to treatment with natural or synthetic retinoids using selected protein biomarkers.

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