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Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma

Item Type:Article
Title:Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor Volasertib in preclinical models of medulloblastoma
Creators Name:Han, Y. and Lindner, S. and Bei, Y. and Garcia, H.D. and Timme, N. and Althoff, K. and Odersky, A. and Schramm, A. and Lissat, A. and Künkele, A. and Deubzer, H.E. and Eggert, A. and Schulte, J.H. and Henssen, A.G.
Abstract:Medulloblastoma is the most prevalent central nervous system tumor in children. Targeted treatment approaches for patients with high-risk medulloblastoma are needed as current treatment regimens are not curative in many cases and cause significant therapy-related morbidity. Medulloblastoma harboring MYC amplification have the most aggressive clinical course and worst outcome. Targeting the BET protein BRD4 has significant anti-tumor effects in preclinical models of MYC-amplified medulloblastoma, however, in most cases these are not curative. We here assessed the therapeutic efficacy of the orally bioavailable BRD4 inhibitor, MK-8628, in preclinical models of medulloblastoma. MK-8628 showed therapeutic efficacy against in vitro and in vivo models of MYC-amplified medulloblastoma by inducing apoptotic cell death and cell cycle arrest. Gene expression analysis of cells treated with MK-8628 showed that anti-tumor effects were accompanied by significant repression of MYC transcription as well as disruption of MYC-regulated transcriptional programs. Additionally, we found that targeting of MYC protein stability through pharmacological PLK1 inhibition showed synergistic anti-medulloblastoma effects when combined with MK-8628 treatment. Thus, MK-8628 is effective against preclinical high-risk medulloblastoma models and its effects can be enhanced through simultaneous targeting of PLK1.
Keywords:BRD4, MYC, PLK1, Pediatric Brain Tumors, Targeted Therapy, Animals, Mice
Source:Cancer Letters
Page Range:24-33
Date:31 March 2019
Official Publication:https://doi.org/10.1016/j.canlet.2018.12.012
PubMed:View item in PubMed

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