Oncotarget

Research Papers:

RITA displays anti-tumor activity in medulloblastomas independent of TP53 status

Aline Gottlieb, Kristina Althoff, Laura Grunewald, Theresa Thor, Andrea Odersky, Marc Schulte, Hedwig E. Deubzer, Lukas Heukamp, Angelika Eggert, Alexander Schramm, Johannes H. Schulte and Annette Künkele _

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Oncotarget. 2017; 8:27882-27891. https://doi.org/10.18632/oncotarget.15840

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Abstract

Aline Gottlieb1, Kristina Althoff1, Laura Grunewald2, Theresa Thor1, Andrea Odersky1, Marc Schulte1, Hedwig E. Deubzer2,3, Lukas Heukamp4, Angelika Eggert2,5,6,7, Alexander Schramm1, Johannes H. Schulte2,5,6, Annette Künkele2,7

1Department of Pediatric Oncology, University Hospital Essen, 45122 Essen, Germany

2Department of Pediatric Oncology, Hematology and SCT, Charité, 13353 Berlin, Germany

3Junior Neuroblastoma Research Group, Experimental and Clinical Research Center of the Max-Delbrück Center for Molecular Medicine (MDC), 13125 Berlin, Germany

4Institute for Pathology, University Hospital of Cologne, 50924 Cologne, Germany

5German Cancer Consortium (DKTK), 69120 Heidelberg, Germany

6German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany

7Berlin Institute of Health (BIH), 10117 Berlin, Germany

Correspondence to:

Annette Künkele, email: Annette.kuenkele@charite.de

Keywords: RITA, medulloblastoma, TP53, MDM2, CDKN1A

Received: September 20, 2016     Accepted: February 20, 2017     Published: March 02, 2017

ABSTRACT

Current therapy of medulloblastoma, the most common malignant brain tumor of childhood, achieves 40–70% survival. Secondary chemotherapy resistance contributes to treatment failure, where TP53 pathway dysfunction plays a key role. MDM2 interaction with TP53 leads to its degradation. Reactivating TP53 functionality using small-molecule inhibitors, such as RITA, to disrupt TP53-MDM2 binding may have therapeutic potential. We show here that RITA decreased viability of all 4 analyzed medulloblastoma cell lines, regardless of TP53 functional status. The decrease in cell viability was accompanied in 3 of the 4 medulloblastoma cell lines by accumulation of TP53 protein in the cells and increased CDKN1A expression. RITA treatment in mouse models inhibited medulloblastoma xenograft tumor growth. These data demonstrate that RITA treatment reduces medulloblastoma cell viability in both in vitro and in vivo models, and acts independently of cellular TP53 status, identifying RITA as a potential therapeutic agent to treat medulloblastoma.


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