Oral Presentation Advances in Neuroblastoma Research Congress 2016

Liquid biopsies reveal exosomal miRNA modulation in high-risk neuroblastoma patients after the induction therapy (#11)

Martina Morini 1 , Davide Cangelosi 1 , Daniela Segalerba 1 , Roberto Luksch 2 , Aurora Castellano 3 , Doriana Fruci 4 , Jaime Font De Mora 5 , Victoria Castel 6 , Adela Cañete 6 , Yania Yanyez 6 , Massimo Conte 7 , Sue Burchill 8 , Martin Elliott 9 , Virginie F. Viprey 9 , Alberto Garaventa 7 , Angela R. Sementa 10 , Maria Corrias 11 , Barbara Carlini 11 , Annalisa Pezzolo 11 , Gudrun Schleiermacher 12 , Angelika Eggert 13 , Vito Pistoia 11 , Luigi Varesio 1
  1. Laboratory of Molecular Biology, Istituto Giannina Gaslini, Genoa, Italy
  2. Pediatric Oncology Department, IRCCS Fondazione Istituto Nazionale dei Tumori, Milan, Italy
  3. Onco-Ematology and Transfusional Medicine Unit, IRCCS Ospedale Bambino Gesù, Rome, Italy
  4. Immuno-Oncology Laboratory, Department of Paediatric Haematology/Oncology, IRCCS Ospedale Bambino Gesù, Rome, Italy
  5. Laboratory of Cellular and Molecular Biology, Center of Translational Medicine, La Fe Hospital Research Institute, Valencia, Spain
  6. Pediatric Oncology Unit, La Fe Hospital Research Institute, Valencia, Spain , Spain
  7. Pediatric Oncology Unit, Istituto Giannina Gaslini, Genoa, Italy
  8. Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, United Kingdom
  9. Cancer Research Unit, Leeds Institute Of Cancer ad Pathology, Leeds, United Kingdom
  10. Anatomical Pathology Unit, Istituto Giannina Gaslini, Genoa, Italy
  11. Laboratory of Oncology, Istituto Giannina Gaslini, Genoa, Italy
  12. Pediatric Oncology Department, Curie Institute, Paris, France
  13. Pediatric Oncology and Hematology, Charitè University Medicine, Berlin, Germany

Introduction

Treatment after induction and prognosis of High-Risk (HR) neuroblastoma (NB) patients depends on their response to a two-month induction-chemotherapy. Unfortunately, there is no early predictive molecular indicator of sensitivity/resistance to treatment. Circulating exosomes are small vesicles which may represent the molecular bioprint of the tumor cells in liquid biopsies. We investigated whether exosomal miRNAs (Exo-miRs) could be an early biomarker of the response to induction-chemotherapy.

Methods

Exosomes were collected before and after the induction-therapy from plasma samples of 50 HR-NB-patients. Exo-miRs expression was measured by RTqPCR on a 381 miRNA panel. Data analyses included feature selection and pathway analysis.

Results

The expression of 24 exo-miRs was significantly modulated (p<0.05, fold-change>1.5) in response to chemotherapy, providing the first indication that exo-miRs may serve as biomarker of the chemotherapic response. Cluster analysis demonstrated that the response to induction was heterogeneous and distinguished at least two groups of patients that may reflect distinct biological and clinical features. Pathway analysis determined whether chemotherapy affected the expression of miRNAs known to be involved in sensitivity/resistance to drugs commonly employed in the induction-chemotherapy. The analysis revealed that 42% of the 24 differentially expressed exo-miRs were associated with sensitivity/resistance to drug response. Mapping the results to individual patients, we clearly identified distinct groups of subjects totally or partially unresponsive/resistant to the induction drugs. The exo-miR profile in the middle phase of the induction therapy is under investigation to find miRNAs possible predictors of the response and that may allow a timely change in the induction protocol for those patients that do not respond to treatment.

Conclusions

We obtained the proof of principle that exo-miRs can represent biomarkers and indicators of sensitivity/resistance to specific drugs for patients with HR-NB. These results pave the way to a broad application of exo-miRs in liquid biopsies applied to neuroblastoma targeted treatment.