Klin Padiatr 2018; 230(03): 169
DOI: 10.1055/s-0038-1645001
Top 3 Solid tumors
Georg Thieme Verlag KG Stuttgart · New York

Preclinical evaluation of BET-inhibition as monotherapy and combination therapy in MYC-driven neuroblastoma

KA Firle
1   Charité Berlin
,
A Szymansky
1   Charité Berlin
,
MJ Witthauer
1   Charité Berlin
,
J Toedling
1   Charité Berlin
2   DKTK, Berlin
,
K Schönbeck
1   Charité Berlin
,
F Hertwig
1   Charité Berlin
2   DKTK, Berlin
,
A Eggert
1   Charité Berlin
2   DKTK, Berlin
,
JH Schulte
1   Charité Berlin
2   DKTK, Berlin
3   DKFZ, Heidelberg, Germany
› Author Affiliations
Further Information

Publication History

Publication Date:
08 May 2018 (online)

Also available at
 

Introduction:

MYC signaling is a predominant driver of high-risk neuroblastoma (NB), caused either by amplification of MYCN or by activation of cMYC. The BET protein BRD4 was shown to cooperate with MYCN in the epigenetic regulation of super-enhancer driven genes in NB. The BET inhibitors OTX015 and JQ1 demonstrated anti-neuroblastoma efficacy. TEN-010 is currently in clinical trials for adult tumors, but its efficacy against NB is yet unknown.

Methods:

72h after treatment with TEN-010, OTX015 or JQ1, we assessed cell viability in NB cell lines using ATP detection. Subsequently, we tested combinations of TEN-010 with conventional chemotherapeutics (e.g. etoposide) and substances interfering with other key pathways (e.g. volasertib).

Results:

Our data indicate a higher specificity for TEN-010, and thus potentially larger therapeutic window. Sensitivity positively correlated with the MYCN/MYC activity score. First results of combinatorial approaches indicate synergistic effects.

Conclusion:

Our results suggest BET inhibition and combination therapies as an effective treatment option that may complement current standard therapy in MYC-driven NB.