RITA displays anti-tumor activity in medulloblastomas independent of TP53 status
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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
Annette Künkele, email: Annette.email@example.com
Keywords: RITA, medulloblastoma, TP53, MDM2, CDKN1A
Received: September 20, 2016 Accepted: February 20, 2017 Published: March 02, 2017
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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