Victor Arnhold is fellow of the BIH Charité Clinician Scientist Program.
Paper of the MonthBIH Academy
JANUARY 2018 – Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma
The Paper of the Month went to Viktor Arnhold and Patrick Hundsdörfer in January.
Viktor Arnhold, Karin Schmelz, Jutta Proba, Annika Winkler, Jasmin Wünschel, Joern Toedling, Hedwig E. Deubzer, Annette Künkele, Angelika Eggert, Johannes H. Schulte1 and Patrick Hundsdoerfer. Reactivating TP53 signaling by the novel MDM2 inhibitor DS-3032b as a therapeutic option for high-risk neuroblastoma. Oncotarget. 2018; 9:2304-2319. https://doi.org/10.18632/oncotarget.23409
Fewer than 50% of patients with high-risk neuroblastoma survive five years after diagnosis with current treatment protocols. Molecular targeted therapies are expected to improve survival. Although MDM2 has been validated as a promising target in preclinical models, no MDM2 inhibitors have yet entered clinical trials for neuroblastoma patients. Toxic side effects, poor bioavailability and low efficacy of the available MDM2 inhibitors that have entered phase I/II trials drive the development of novel MDM2 inhibitors with an improved risk-benefit profile. We investigated the effect of the novel MDM2 small molecular inhibitor, DS-3032b, on viability, proliferation, senescence, migration, cell cycle arrest and apoptosis in a panel of six neuroblastoma cell lines with different TP53 and MYCN genetic backgrounds, and assessed efficacy in a murine subcutaneous model for high-risk neuroblastoma. Re-analysis of existing expression data from 476 primary neuroblastomas showed that high-level MDM2 expression correlated with poor patient survival. DS-3032b treatment enhanced TP53 target gene expression and induced G1 cell cycle arrest, senescence and apoptosis. CRISPR-mediated MDM2 knockout in neuroblastoma cells mimicked DS-3032b treatment. TP53 signaling was selectively activated by DS-3032b in neuroblastoma cells with wildtype TP53, regardless of the presence of MYCN amplification, but was significantly reduced by TP53 mutations or expression of a dominant-negative TP53 mutant. Oral DS-3032b administration inhibited xenograft tumor growth and prolonged mouse survival. Our in vitro and in vivo data demonstrate that DS-3032b reactivates TP53 signaling even in the presence of MYCN amplification in neuroblastoma cells, to reduce proliferative capacity and cause cytotoxicity.
In January, the team around Patrick Hundsdörfer and BIH Charité Clinician Scientist Viktor Arnhold received the Paper of the Month award. We have previously spoken with them about their research and the paper.
What is at the focus of your research?
We are researching new therapy approaches for the treatment of children and adolescents with cancer. Neuroblastoma, one of the most common childhood tumors, is the central focus of our research group. The aim of our research is to improve treatment options and thus to improve the chances of recovery, and at the same time, to reduce the side effects associated with therapy.
What motivates you to perform this research?
This work focuses on the transcription factor p53, the deactivation of which often leads to the uncontrolled growth of neuroblastoma cells. We were able to show, in both cell culture models and animal models, that tumor cell growth is inhibited by the substance DS-3032b. We were also able to identify the initiation of cell death (apoptosis) as the most important mechanism of growth inhibition.
Which cooperation partners have contributed to the publication? Who was significantly involved?
This work resulted from the close cooperation between the individual research groups within the department of Pediatric Oncology at Charité. In addition to our research group, the working groups around Prof. Dr. Schulte, PD Dr. Deubzer, and Dr. Künkele were involved.
What are the next steps planned for the project and what are the possible implications of your results for patients?
In the next stage, we will investigate how the reactivation of p53 via DS-3032b can be combined with conventional cytostatics and other “small molecules” to identify the distinctions between the various therapeutic approaches. The most promising combination therapy is to then be tested in a Phase I/II clinical trial on children with neuroblastoma who do not respond to other therapies, or for whom conventional therapies have significant side effects.