In:
Cancer Research, American Association for Cancer Research (AACR), Vol. 74, No. 19_Supplement ( 2014-10-01), p. 3967-3967
Kurzfassung:
Neuroblastomas harboring MYCN amplifications are highly lethal tumors. They are often resistant to standard chemotherapy, yet the development of targeted therapies has been hampered by a lack of compounds targeting MYCN. We and others have recently discovered that targeting BET bromodomain proteins, especially BRD4, disrupts epigenetic regulation of MYCN and its targets in neuroblastoma. OTX015, a new BET protein inhibitor, is the first lead into clinical phase I/II trials and has shown promising pharmacological properties in adults. Here, we investigate the preclinical efficacy of OTX015 in MYCN-amplified neuroblastoma. We tested in vitro OTX015 efficacy in 6 established neuroblastoma (NB) cell lines. We performed cell cycle profiling and analyzed markers for apoptosis and proliferation after 72h-treatment at 500 nM OTX015. The effect of OTX015 on MYCN expression and global MYCN-associated transcriptional activity was assessed by quantitative real time PCR and gene expression microarray profiling, respectively. In vivo efficacy of orally OTX015 was assessed in IMR5 xenografts, a N-MYC driven NB model, using diffent treatment schedules (50mg/kg/day, 100mg/kg/day and 50mg/kg/bidaily). Treatment of MYCN-amplified neuroblastoma cells with OTX015 resulted in decreased cell viability, induction of apoptosis and reduced proliferation. Concentrations of 50% inhibition (IC50) ranged between 50nM and 500nM. OTX015 treatment also resulted in an increase in the percentage of cells in G1 phase. This corresponded with the downregulation of MYCN mRNA and protein levels and MYCN-associated transcriptional activity. Interestigly, MYCN amplified cell lines were most sensitive to OTX015 treatment. In contrast, no effect was observed with OTX15 on normal cells. In vivo treatment with OTX015, significantly decreased tumor burden after 4 weeks and prolonged survival as compared to vehicle-treated mice. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYCN-driven neuroblastomas and serve as rationale to move forward with early phase clinical trials for children with these highly lethal tumors. Citation Format: Johannes H. Schulte, Kristina Althoff, Emma Bell, Andrea Odersky, Anneleen Beckers, Frank Speleman, Simon Schäfers, Alexander Schramm, Angelika Eggert, Frank Westermann, Eugenia Riveiro, Esteban Cvitkovic, Anton Henssen. BET protein inhibitor OTX015 has selective anti-tumoral activity in preclinical models of MYCN- amplified neuroblastoma. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3967. doi:10.1158/1538-7445.AM2014-3967
Materialart:
Online-Ressource
ISSN:
0008-5472
,
1538-7445
DOI:
10.1158/1538-7445.AM2014-3967
Sprache:
Englisch
Verlag:
American Association for Cancer Research (AACR)
Publikationsdatum:
2014
ZDB Id:
2036785-5
ZDB Id:
1432-1
ZDB Id:
410466-3
