Oncotarget

Research Papers:

Personalized therapy: CNS HGNET-BCOR responsiveness to arsenic trioxide combined with radiotherapy

Claudia Paret _, Alexandra Russo, Henrike Otto, Arnulf Mayer, Sebastian Zahnreich, Wolfgang Wagner, David Samuel, David Scharnhorst, David A. Solomon, Girish Dhall, Kenneth Wong, Hannah Bender, Francesca Alt, Arthur Wingerter, Marie A. Neu, Olaf Beck, Dirk Prawitt, Stefan Eder, Nicole Henninger, Khalifa El Malki, Nadine Lehmann, Nora Backes, Lea Roth, Larissa Seidmann, Clemens Sommer, Marc A. Brockmann, Gundula Staatz, Heinz Schmidberger and Jörg Faber

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Oncotarget. 2017; 8:114210-114225. https://doi.org/10.18632/oncotarget.23174

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Abstract

Claudia Paret1,14,*, Alexandra Russo1,14,*, Henrike Otto1,14, Arnulf Mayer2, Sebastian Zahnreich2, Wolfgang Wagner3, David Samuel4, David Scharnhorst5, David A. Solomon6, Girish Dhall7, Kenneth Wong8, Hannah Bender1, Francesca Alt1,14, Arthur Wingerter1,14, Marie A. Neu1,14, Olaf Beck1,14, Dirk Prawitt9, Stefan Eder1,14, Nicole Henninger1,14, Khalifa El Malki1,14, Nadine Lehmann1,14, Nora Backes1,14, Lea Roth1,14, Larissa Seidmann10, Clemens Sommer11, Marc A. Brockmann12, Gundula Staatz13, Heinz Schmidberger2 and Jörg Faber1,14

1Section of Pediatric Oncology, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Mainz, Germany

2Department of Radiation Oncology and Radiation Therapy, University Medical Center of The Johannes Gutenberg University Mainz, Mainz, Germany

3Section of Pediatric Neurosurgery, Department of Neurosurgery, University Medical Center of The Johannes Gutenberg University Mainz, Mainz, Germany

4Department of Oncology, Valley Children’s Hospital, Madera, California, USA

5Department of Pathology, Valley Children’s Hospital, Madera, California, USA

6Division of Neuropathology, University of California, San Francisco, California, USA

7Division of Hematology, Oncology and Blood & Marrow Transplantation, Children’s Hospital Los Angeles, Los Angeles, California, USA

8Children's Center for Cancer and Blood Diseases, Children's Hospital Los Angeles, Los Angeles, California, USA

9Center for Pediatrics and Adolescent Medicine, Children's Hospital, University Medical Center of The Johannes Gutenberg University Mainz, Mainz, Germany

10Institute of Pathology, University Medical Center of The Johannes Gutenberg University Mainz, Mainz, Germany

11Division of Neuropathology, University Medical Center of The Johannes Gutenberg University Mainz, Mainz, Germany

12Department of Neuroradiology, University Medical Center of The Johannes Gutenberg University Mainz, Mainz, Germany

13Section of Pediatric Radiology, Department of Diagnostic and Interventional Radiology, University Medical Center of The Johannes Gutenberg University Mainz, Mainz, Germany

14University Cancer Center of The Johannes Gutenberg University, Mainz, Germany

*These authors have contributed equally to the work

Correspondence to:

Claudia Paret, email: claudia.paret@unimedizin-mainz.de

Keywords: ATO; HGNET-BCOR; radiation; liquid biopsy; targeted therapy

Received: August 09, 2017     Accepted: November 16, 2017     Published: December 11, 2017

ABSTRACT

High-grade neuroepithelial tumor of the central nervous system with BCOR alteration (HGNET-BCOR) is a rare, highly malignant tumor. At the time of this publication, no standard protocol exists to treat this tumor entity. In this work, we tested the responsiveness of the primary culture PhKh1 derived from tumor tissue from a pediatric HGNET-BCOR patient (P1) to inhibitors of the Sonic hedgehog pathway combined with radiation. The SMO inhibitors vismodegib and itraconazole had low effect on the proliferation of the PhKh1 cells. However, the GLI inhibitor arsenic trioxide reduced the expression of GLI target genes in the PhKh1 cells and in combination with radiotherapy significantly decreased their clonogenic potential. PhKh1 cells resistant to arsenic trioxide were characterized by the overexpression of molecular chaperones. We combined arsenic trioxide and radiation in the relapse therapy protocol of P1, achieving complete remission after seven weeks. Clinical remission lasted for six months, when P1 developed systemic metastases. Meanwhile, an increase in the concentration of circulating tumor DNA carrying a BCOR internal tandem duplication was observed. Molecular characterization of a second patient (P2) was also performed. In P2, we detected a larger tandem duplication and greater activation of the Sonic hedgehog pathway than in P1. These findings suggest that combining arsenic trioxide with radiotherapy may represent a new therapeutic approach. Moreover, peripheral blood analysis for circulating tumor DNA could help in the early detection of systemic metastases.


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