MB-108EXPRESSION OF TROPOMYOSIN RECEPTOR KINASE C (TrkC) HAS NO MAJOR IMPACT ON THE RESPONSE TO THERAPY OF MEDULLOBLASTOMA IN VITRO AND IN A CLINICAL PATIENT COHORT

Abstract

MB-108. EXPRESSION OF TROPOMYOSIN RECEPTOR KINASE C (TrkC) HAS NO MAJOR IMPACT ON THE RESPONSE TO THERAPY OF MEDULLOBLASTOMA IN VITRO AND IN A CLINICAL PATIENT COHORT Carsten Friedrich1, Tarek Shalaby2, Christoph Oehler3,4, Martin Pruschy5, Burkhardt Seifert6, Monika Warmuth-Metz7, Rolf-Dieter Kortmann8, Stefan Rutkowski9, Michael A. Grotzer2, and Andre O. von Bueren10,11; Division of Pediatric Oncology, Hematology and Hemostaseology, Department of Woman’s and Children’s Health, University Hospital Leipzig, Leipzig, Germany; Department of Oncology, University Children’s Hospital, Zurich, Switzerland; Department of Radiation Oncology, University Hospital Zurich, Zurich, Switzerland; Department of Radiation Oncology, Hospital Graubuenden, Chur, Switzerland; Laboratory for Molecular Radiobiology, Radiation Oncology, University Hospital Zurich, Zurich, Switzerland; Department of Biostatistics; Epidemiology, Biostatistics and Prevention Institute, University of Zurich, Zurich, Switzerland; Department of Neuroradiology, University of Wuerzburg, Wuerzburg, Germany; Department of Radiation Oncology, University of Leipzig, Leipzig, Germany; Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Department of Pediatrics, Division of Pediatric Hematology and Oncology, University Medical Center Goettingen, Goettingen, Germany; Department of Pediatrics and Adolescent Medicine, Division of Pediatric Hematology and Oncology, University Hospital of Geneva, Geneva, Switzerland BACKGROUND: High mRNA expression of the tropomyosin receptor kinase C (TrkC) has been associated with favorable survival in medulloblastoma patients. A not yet tested explanation could be that TrkC mRNA expression modulates the response to therapy. PATIENTS AND METHODS: Medulloblastoma-derived cell line DAOY, stably transfected to overexpress TrkC (clone DAOY-TrkC) and compared to a control (clone DAOY-EV, empty vector transfected), was grown under serum-free conditions (+ TrkC ligand neutrophin-3, NT-3) and cell viability was tested after irradiation or incubation with chemotherapeutic drugs after 72 h using the MTS-assay. Neuroradiologic response topostoperativechemotherapyorcraniospinal irradiation (CSI) of medulloblastoma patients aged 3-21 years with postoperative residual disease treated within the consecutive trials HIT’91/HIT2000 was compared to TrkC mRNA expression in their tumor samples. RESULTS: Cell viability of DAOY-TrkC compared to DAOY-EV was not different after incubation with increasing doses of cisplatin (0-4.8 mg/ml), etoposide (0-1.3 mg/ml), or vincristine (0-20 ng/ml), and irradiation (2, 5, 10 Gy). WhileTrkC mRNAexpression tended tobe higher in non-responders (n 1⁄4 5/19) to postoperative CSI (p 1⁄4 0.03, ratio 15.5, 95% CI 9-267), this was the case in responders (n 1⁄4 23/43) to chemotherapy (p 1⁄4 0.04, ratio 6.1, 95% CI 1.1-35, both analyzed with Mann-Withney U test and not significant after Bonferroni adjustment). CONCLUSIONS: TrkC mRNA expression was not associated with a considerable improvement in response to therapy neither in vitro nor in a MB patient cohort. The study is limited by a relatively small medulloblastoma patient cohort and the availability of only one TrkC mRNA overexpressing medulloblastoma cell line. Neuro-Oncology 18:iii97–iii122, 2016. doi:10.1093/neuonc/now076.103 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.