TY  - JOUR
AU  - Valinciute, Gintvile
AU  - Ecker, Jonas
AU  - Selt, Florian
AU  - Hielscher, Thomas
AU  - Sigaud, Romain
AU  - Ridinger, Johannes
AU  - Thatikonda, Venu
AU  - Gatzweiler, Charlotte
AU  - Robinson, Sarah
AU  - Talbot, Julie
AU  - Bernardi, Flavia
AU  - Picard, Daniel
AU  - Blattner-Johnson, Mirjam
AU  - Schmid, Simone
AU  - Jones, David T
AU  - van Tilburg, Cornelis M
AU  - Capper, David
AU  - Kool, Marcel
AU  - Remke, Marc
AU  - Oehme, Ina
AU  - Pfister, Stefan M
AU  - Roussel, Martine F
AU  - Ayrault, Olivier
AU  - Witt, Olaf
AU  - Milde, Till
TI  - Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells.
JO  - Journal of neuro-oncology
VL  - 163
IS  - 1
SN  - 0167-594x
CY  - Dordrecht [u.a.]
PB  - Springer Science + Business Media B.V
M1  - DKFZ-2023-00984
SP  - 143-158
PY  - 2023
N1  - #EA:B310#LA:B310# / 2023 May;163(1):143-158
AB  - We and others have demonstrated that MYC-amplified medulloblastoma (MB) cells are susceptible to class I histone deacetylase inhibitor (HDACi) treatment. However, single drug treatment with HDACi has shown limited clinical efficacy. We hypothesized that addition of a second compound acting synergistically with HDACi may enhance efficacy.We used a gene expression dataset to identify PLK1 as a second target in MB cells and validated the relevance of PLK1 in MB. We measured cell metabolic activity, viability, and cycle progression in MB cells after treatment with PLK1-specific inhibitors (PLK1i). Chou-Talalay synergy calculations were used to determine the nature of class I HDACi entinostat and PLK1i interaction which was validated. Finally, the clinical potential of the combination was assessed in the in vivo experiment.MYC-amplified tumor cells are highly sensitive towards treatment with ATP-competitive PLK1i as a monotherapy. Entinostat and PLK1i in combination act synergistically in MYC-driven MB cells, exerting cytotoxic effects at clinically relevant concentrations. The downstream effect is exerted via MYC-related pathways, pointing out the potential of MYC amplification as a clinically feasible predictive biomarker for patient selection. While entinostat significantly extended survival of mice implanted with orthotopic MYC-amplified MB PDX, there was no evidence of the improvement of survival when treating the animals with the combination.The combination of entinostat and PLK1i showed synergistic interaction in vitro, but not in vivo. Therefore, further screening of blood-brain barrier penetrating PLK1i is warranted to determine the true potential of the combination as no on-target activity was observed after PLK1i volasertib treatment in vivo.
KW  - HDAC inhibitor (Other)
KW  - MYC (Other)
KW  - Medulloblastoma (Other)
KW  - PLK1 inhibitor (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:37183219
DO  - DOI:10.1007/s11060-023-04319-1
UR  - https://inrepo02.dkfz.de/record/276078
ER  -