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Open Access 15-05-2023 | Medulloblastoma | Research

Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells

Authors: Gintvile Valinciute, Jonas Ecker, Florian Selt, Thomas Hielscher, Romain Sigaud, Johannes Ridinger, Venu Thatikonda, Charlotte Gatzweiler, Sarah Robinson, Julie Talbot, Flavia Bernardi, Daniel Picard, Mirjam Blattner-Johnson, Simone Schmid, David T. Jones, Cornelis M. van Tilburg, David Capper, Marcel Kool, Marc Remke, Ina Oehme, Stefan M. Pfister, Martine F. Roussel, Olivier Ayrault, Olaf Witt, Till Milde

Published in: Journal of Neuro-Oncology | Issue 1/2023

Abstract

Purpose

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.

Methods

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.

Results

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.

Conclusion

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.

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Ostrom QT, Cioffi G, Gittleman H, Patil N, Waite K, Kruchko C, Barnholtz-Sloan JS (2019) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol 21:v1–v100. https://doi.org/10.1093/neuonc/noz150CrossRefPubMedPubMedCentral

Cavalli FMG, Remke M, Rampasek L, Peacock J, Shih DJH, Luu B, Garzia L, Torchia J, Nor C, Morrissy AS, Agnihotri S, Thompson YY, Kuzan-Fischer CM, Farooq H, Isaev K, Daniels C, Cho BK, Kim SK, Wang KC, Lee JY, Grajkowska WA, Perek-Polnik M, Vasiljevic A, Faure-Conter C, Jouvet A, Giannini C, Nageswara Rao AA, Li KKW, Ng HK, Eberhart CG, Pollack IF, Hamilton RL, Gillespie GY, Olson JM, Leary S, Weiss WA, Lach B, Chambless LB, Thompson RC, Cooper MK, Vibhakar R, Hauser P, van Veelen MC, Kros JM, French PJ, Ra YS, Kumabe T, Lopez-Aguilar E, Zitterbart K, Sterba J, Finocchiaro G, Massimino M, Van Meir EG, Osuka S, Shofuda T, Klekner A, Zollo M, Leonard JR, Rubin JB, Jabado N, Albrecht S, Mora J, Van Meter TE, Jung S, Moore AS, Hallahan AR, Chan JA, Tirapelli DPC, Carlotti CG, Fouladi M, Pimentel J, Faria CC, Saad AG, Massimi L, Liau LM, Wheeler H, Nakamura H, Elbabaa SK, Perezpena-Diazconti M, de Leon FCP, Robinson S, Zapotocky M, Lassaletta A, Huang A, Hawkins CE, Tabori U, Bouffet E, Bartels U, Dirks PB, Rutka JT, Bader GD, Reimand J, Goldenberg A, Ramaswamy V, Taylor MD (2017) Intertumoral heterogeneity within medulloblastoma subgroups. Cancer Cell 31:737–754. https://doi.org/10.1016/j.ccell.2017.05.005CrossRefPubMedPubMedCentral

Taylor MD, Northcott PA, Korshunov A, Remke M, Cho YJ, Clifford SC, Eberhart CG, Parsons DW, Rutkowski S, Gajjar A, Ellison DW, Lichter P, Gilbertson RJ, Pomeroy SL, Kool M, Pfister SM (2012) Molecular subgroups of medulloblastoma: the current consensus. Acta Neuropathol 123:465–472. https://doi.org/10.1007/s00401-011-0922-zCrossRefPubMed

Schwalbe EC, Lindsey JC, Nakjang S, Crosier S, Smith AJ, Hicks D, Rafiee G, Hill RM, Iliasova A, Stone T, Pizer B, Michalski A, Joshi A, Wharton SB, Jacques TS, Bailey S, Williamson D, Clifford SC (2017) Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncol 18:958–971. https://doi.org/10.1016/S1470-2045(17)30243-7CrossRefPubMedPubMedCentral

Northcott PA, Buchhalter I, Morrissy AS, Hovestadt V, Weischenfeldt J, Ehrenberger T, Grobner S, Segura-Wang M, Zichner T, Rudneva VA, Warnatz HJ, Sidiropoulos N, Phillips AH, Schumacher S, Kleinheinz K, Waszak SM, Erkek S, Jones DTW, Worst BC, Kool M, Zapatka M, Jager N, Chavez L, Hutter B, Bieg M, Paramasivam N, Heinold M, Gu Z, Ishaque N, Jager-Schmidt C, Imbusch CD, Jugold A, Hubschmann D, Risch T, Amstislavskiy V, Gonzalez FGR, Weber UD, Wolf S, Robinson GW, Zhou X, Wu G, Finkelstein D, Liu Y, Cavalli FMG, Luu B, Ramaswamy V, Wu X, Koster J, Ryzhova M, Cho YJ, Pomeroy SL, Herold-Mende C, Schuhmann M, Ebinger M, Liau LM, Mora J, McLendon RE, Jabado N, Kumabe T, Chuah E, Ma Y, Moore RA, Mungall AJ, Mungall KL, Thiessen N, Tse K, Wong T, Jones SJM, Witt O, Milde T, Von Deimling A, Capper D, Korshunov A, Yaspo ML, Kriwacki R, Gajjar A, Zhang J, Beroukhim R, Fraenkel E, Korbel JO, Brors B, Schlesner M, Eils R, Marra MA, Pfister SM, Taylor MD, Lichter P (2017) The whole-genome landscape of medulloblastoma subtypes. Nature 547:311–317. https://doi.org/10.1038/nature22973CrossRefPubMedPubMedCentral

Sharma T, Schwalbe EC, Williamson D, Sill M, Hovestadt V, Mynarek M, Rutkowski S, Robinson GW, Gajjar A, Cavalli F, Ramaswamy V, Taylor MD, Lindsey JC, Hill RM, Jager N, Korshunov A, Hicks D, Bailey S, Kool M, Chavez L, Northcott PA, Pfister SM, Clifford SC (2019) Second-generation molecular subgrouping of medulloblastoma: an international meta-analysis of group 3 and group 4 subtypes. Acta Neuropathol 138:309–326. https://doi.org/10.1007/s00401-019-02020-0CrossRefPubMedPubMedCentral

Park AK, Lee SJ, Phi JH, Wang KC, Kim DG, Cho BK, Haberler C, Fattet S, Dufour C, Puget S, Sainte-Rose C, Bourdeaut F, Grill J, Delattre O, Kim SK, Park WY (2012) Prognostic classification of pediatric medulloblastoma based on chromosome 17p loss, expression of MYCC and MYCN, and wnt pathway activation. Neuro Oncol 14:203–214. https://doi.org/10.1093/neuonc/nor196CrossRefPubMed

Allen-Petersen BL, Sears RC (2019) Mission possible: advances in MYC therapeutic targeting in cancer. BioDrugs 33:539–553. https://doi.org/10.1007/s40259-019-00370-5CrossRefPubMedPubMedCentral

Witt O, Deubzer HE, Milde T, Oehme I (2009) HDAC family: what are the cancer relevant targets? Cancer Lett 277:8–21. https://doi.org/10.1016/j.canlet.2008.08.016CrossRefPubMed

10.

Ecker J, Oehme I, Mazitschek R, Korshunov A, Kool M, Hielscher T, Kiss J, Selt F, Konrad C, Lodrini M, Deubzer HE, von Deimling A, Kulozik AE, Pfister SM, Witt O, Milde T (2015) Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma. Acta Neuropathol Commun 3:22. https://doi.org/10.1186/s40478-015-0201-7CrossRefPubMedPubMedCentral

11.

Pei Y, Liu KW, Wang J, Garancher A, Tao R, Esparza LA, Maier DL, Udaka YT, Murad N, Morrissy S, Seker-Cin H, Brabetz S, Qi L, Kogiso M, Schubert S, Olson JM, Cho YJ, Li XN, Crawford JR, Levy ML, Kool M, Pfister SM, Taylor MD, Wechsler-Reya RJ (2016) HDAC and PI3K antagonists cooperate to inhibit growth of MYC-driven medulloblastoma. Cancer Cell 29:311–323. https://doi.org/10.1016/j.ccell.2016.02.011CrossRefPubMedPubMedCentral

12.

Ecker J, Thatikonda V, Sigismondo G, Selt F, Valinciute G, Oehme I, Müller C, Buhl JL, Ridinger J, Usta D, Qin N, van Tilburg CM, Herold-Mende C, Remke M, Sahm F, Westermann F, Kool M, Wechsler-Reya RJ, Chavez L, Krijgsveld J, Jäger N, Pfister SM, Witt O, Milde T (2021) Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma. Neuro Oncol 23:226–239. https://doi.org/10.1093/neuonc/noaa191CrossRefPubMed

13.

Eckschlager T, Plch J, Stiborova M, Hrabeta J (2017) Histone deacetylase inhibitors as anticancer drugs. Int J Mol Sci 18:1414. https://doi.org/10.3390/ijms18071414CrossRefPubMedPubMedCentral

14.

Zitouni S, Nabais C, Jana SC, Guerrero A, Bettencourt-Dias M (2014) Polo-like kinases: structural variations lead to multiple functions. Nat Rev Mol Cell Biol 15:433–452. https://doi.org/10.1038/nrm3819CrossRefPubMed

15.

de Carcer G, Venkateswaran SV, Salgueiro L, El Bakkali A, Somogyi K, Rowald K, Montanes P, Sanclemente M, Escobar B, de Martino A, McGranahan N, Malumbres M, Sotillo R (2018) Plk1 overexpression induces chromosomal instability and suppresses tumor development. Nat Commun 9:3012. https://doi.org/10.1038/s41467-018-05429-5CrossRefPubMedPubMedCentral

16.

Pajtler KW, Sadowski N, Ackermann S, Althoff K, Schonbeck K, Batzke K, Schafers S, Odersky A, Heukamp L, Astrahantseff K, Kunkele A, Deubzer HE, Schramm A, Sprussel A, Thor T, Lindner S, Eggert A, Fischer M, Schulte JH (2017) The GSK461364 PLK1 inhibitor exhibits strong antitumoral activity in preclinical neuroblastoma models. Oncotarget 8:6730–6741. https://doi.org/10.18632/oncotarget.14268CrossRefPubMed

17.

Rudolph D, Steegmaier M, Hoffmann M, Grauert M, Baum A, Quant J, Haslinger C, Garin-Chesa P, Adolf GR (2009) BI 6727, a polo-like kinase inhibitor with improved pharmacokinetic profile and broad antitumor activity. Clin Cancer Res 15:3094–3102. https://doi.org/10.1158/1078-0432.CCR-08-2445CrossRefPubMed

18.

Dohner H, Lubbert M, Fiedler W, Fouillard L, Haaland A, Brandwein JM, Lepretre S, Reman O, Turlure P, Ottmann OG, Muller-Tidow C, Kramer A, Raffoux E, Dohner K, Schlenk RF, Voss F, Taube T, Fritsch H, Maertens J (2014) Randomized, phase 2 trial of low-dose cytarabine with or without volasertib in AML patients not suitable for induction therapy. Blood 124:1426–1433. https://doi.org/10.1182/blood-2014-03-560557CrossRefPubMedPubMedCentral

19.

Korshunov A, Witt H, Hielscher T, Benner A, Remke M, Ryzhova M, Milde T, Bender S, Wittmann A, Schottler A, Kulozik AE, Witt O, von Deimling A, Lichter P, Pfister S (2010) Molecular staging of intracranial ependymoma in children and adults. J Clin Oncol 28:3182–3190. https://doi.org/10.1200/JCO.2009.27.3359CrossRefPubMed

20.

Milde T, Lodrini M, Savelyeva L, Korshunov A, Kool M, Brueckner LM, Antunes AS, Oehme I, Pekrun A, Pfister SM, Kulozik AE, Witt O, Deubzer HE (2012) HD-MB03 is a novel group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J Neuro Oncol 110:335–348. https://doi.org/10.1007/s11060-012-0978-1CrossRef

21.

Bai AH, Milde T, Remke M, Rolli CG, Hielscher T, Cho YJ, Kool M, Northcott PA, Jugold M, Bazhin AV, Eichmuller SB, Kulozik AE, Pscherer A, Benner A, Taylor MD, Pomeroy SL, Kemkemer R, Witt O, Korshunov A, Lichter P, Pfister SM (2012) MicroRNA-182 promotes leptomeningeal spread of non-sonic hedgehog-medulloblastoma. Acta Neuropathol 123:529–538. https://doi.org/10.1007/s00401-011-0924-xCrossRefPubMed

22.

Mynarek M, Obrecht D, Sill M, Sturm D, Kloth-Stachnau K, Selt F, Ecker J, von Hoff K, Juhnke BO, Goschzik T, Pietsch T, Bockmayr M, Kool M, von Deimling A, Witt O, Schüller U, Benesch M, Gerber NU, Sahm F, Jones DTW, Korshunov A, Pfister SM, Rutkowski S, Milde T (2023) Identification of low and very high-risk patients with non-WNT/non-SHH medulloblastoma by improved clinico-molecular stratification of the HIT2000 and I-HIT-MED cohorts. Acta Neuropathol 145:97–112. https://doi.org/10.1007/s00401-022-02522-4CrossRefPubMed

23.

Capper D, Jones DTW, Sill M, Hovestadt V, Schrimpf D, Sturm D, Koelsche C, Sahm F, Chavez L, Reuss DE, Kratz A, Wefers AK, Huang K, Pajtler KW, Schweizer L, Stichel D, Olar A, Engel NW, Lindenberg K, Harter PN, Braczynski AK, Plate KH, Dohmen H, Garvalov BK, Coras R, Hölsken A, Hewer E, Bewerunge-Hudler M, Schick M, Fischer R, Beschorner R, Schittenhelm J, Staszewski O, Wani K, Varlet P, Pages M, Temming P, Lohmann D, Selt F, Witt H, Milde T, Witt O, Aronica E, Giangaspero F, Rushing E, Scheurlen W, Geisenberger C, Rodriguez FJ, Becker A, Preusser M, Haberler C, Bjerkvig R, Cryan J, Farrell M, Deckert M, Hench J, Frank S, Serrano J, Kannan K, Tsirigos A, Brück W, Hofer S, Brehmer S, Seiz-Rosenhagen M, Hänggi D, Hans V, Rozsnoki S, Hansford JR, Kohlhof P, Kristensen BW, Lechner M, Lopes B, Mawrin C, Ketter R, Kulozik A, Khatib Z, Heppner F, Koch A, Jouvet A, Keohane C, Mühleisen H, Mueller W, Pohl U, Prinz M, Benner A, Zapatka M, Gottardo NG, Driever PH, Kramm CM, Müller HL, Rutkowski S, von Hoff K, Frühwald MC, Gnekow A, Fleischhack G, Tippelt S, Calaminus G, Monoranu CM, Perry A, Jones C, Jacques TS, Radlwimmer B, Gessi M, Pietsch T, Schramm J, Schackert G, Westphal M, Reifenberger G, Wesseling P, Weller M, Collins VP, Blümcke I, Bendszus M, Debus J, Huang A, Jabado N, Northcott PA, Paulus W, Gajjar A, Robinson GW, Taylor MD, Jaunmuktane Z, Ryzhova M, Platten M, Unterberg A, Wick W, Karajannis MA, Mittelbronn M, Acker T, Hartmann C, Aldape K, Schüller U, Buslei R, Lichter P, Kool M, Herold-Mende C, Ellison DW, Hasselblatt M, Snuderl M, Brandner S, Korshunov A, von Deimling A, Pfister SM (2018) DNA methylation-based classification of central nervous system tumours. Nature 555:469–474. https://doi.org/10.1038/nature26000CrossRefPubMedPubMedCentral

24.

Rettig I, Koeneke E, Trippel F, Mueller WC, Burhenne J, Kopp-Schneider A, Fabian J, Schober A, Fernekorn U, von Deimling A, Deubzer HE, Milde T, Witt O, Oehme I (2015) Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation. Cell Death Dis 6:e1657. https://doi.org/10.1038/cddis.2015.24CrossRefPubMedPubMedCentral

25.

Schmitt M, Pawlita M (2009) High-throughput detection and multiplex identification of cell contaminations. Nucleic Acids Res 37:e119. https://doi.org/10.1093/nar/gkp581CrossRefPubMedPubMedCentral

26.

Liberzon A, Birger C, Thorvaldsdottir H, Ghandi M, Mesirov JP, Tamayo P (2015) The molecular signatures database (MSigDB) hallmark gene set collection. Cell Syst 1:417–425. https://doi.org/10.1016/j.cels.2015.12.004CrossRefPubMedPubMedCentral

27.

Worst BC, van Tilburg CM, Balasubramanian GP, Fiesel P, Witt R, Freitag A, Boudalil M, Previti C, Wolf S, Schmidt S, Chotewutmontri S, Bewerunge-Hudler M, Schick M, Schlesner M, Hutter B, Taylor L, Borst T, Sutter C, Bartram CR, Milde T, Pfaff E, Kulozik AE, von Stackelberg A, Meisel R, Borkhardt A, Reinhardt D, Klusmann JH, Fleischhack G, Tippelt S, Dirksen U, Jurgens H, Kramm CM, von Bueren AO, Westermann F, Fischer M, Burkhardt B, Wossmann W, Nathrath M, Bielack SS, Fruhwald MC, Fulda S, Klingebiel T, Koscielniak E, Schwab M, Tremmel R, Driever PH, Schulte JH, Brors B, von Deimling A, Lichter P, Eggert A, Capper D, Pfister SM, Jones DT, Witt O (2016) Next-generation personalised medicine for high-risk paediatric cancer patients - the INFORM pilot study. Eur J Cancer 65:91–101. https://doi.org/10.1016/j.ejca.2016.06.009CrossRefPubMed

28.

Archer TC, Ehrenberger T, Mundt F, Gold MP, Krug K, Mah CK, Mahoney EL, Daniel CJ, LeNail A, Ramamoorthy D, Mertins P, Mani DR, Zhang H, Gillette MA, Clauser K, Noble M, Tang LC, Pierre-François J, Silterra J, Jensen J, Tamayo P, Korshunov A, Pfister SM, Kool M, Northcott PA, Sears RC, Lipton JO, Carr SA, Mesirov JP, Pomeroy SL, Fraenkel E (2018) Proteomics, post-translational modifications, and integrative analyses reveal molecular heterogeneity within medulloblastoma subgroups. Cancer Cell 34:396-410e398. https://doi.org/10.1016/j.ccell.2018.08.004CrossRefPubMedPubMedCentral

29.

Forget A, Martignetti L, Puget S, Calzone L, Brabetz S, Picard D, Montagud A, Liva S, Sta A, Dingli F, Arras G, Rivera J, Loew D, Besnard A, Lacombe J, Pages M, Varlet P, Dufour C, Yu H, Mercier AL, Indersie E, Chivet A, Leboucher S, Sieber L, Beccaria K, Gombert M, Meyer FD, Qin N, Bartl J, Chavez L, Okonechnikov K, Sharma T, Thatikonda V, Bourdeaut F, Pouponnot C, Ramaswamy V, Korshunov A, Borkhardt A, Reifenberger G, Poullet P, Taylor MD, Kool M, Pfister SM, Kawauchi D, Barillot E, Remke M, Ayrault O (2018) Aberrant ERBB4-SRC signaling as a hallmark of group 4 medulloblastoma revealed by integrative phosphoproteomic profiling. Cancer Cell 34:379–395. https://doi.org/10.1016/j.ccell.2018.08.002CrossRefPubMed

30.

Schmidt C, Schubert NA, Brabetz S, Mack N, Schwalm B, Chan JA, Selt F, Herold-Mende C, Witt O, Milde T, Pfister SM, Korshunov A, Kool M (2017) Preclinical drug screen reveals topotecan, actinomycin D, and volasertib as potential new therapeutic candidates for ETMR brain tumor patients. Neuro Oncol 19:1607–1617. https://doi.org/10.1093/neuonc/nox093CrossRefPubMedPubMedCentral

31.

Chou TC (2006) Theoretical basis, experimental design, and computerized simulation of synergism and antagonism in drug combination studies. Pharmacol Rev 58:621–681. https://doi.org/10.1124/pr.58.3.10CrossRefPubMed

32.

Schoffski P, Awada A, Dumez H, Gil T, Bartholomeus S, Wolter P, Taton M, Fritsch H, Glomb P, Munzert G (2012) A phase I, dose-escalation study of the novel polo-like kinase inhibitor volasertib (BI 6727) in patients with advanced solid tumours. Eur J Cancer 48:179–186. https://doi.org/10.1016/j.ejca.2011.11.001CrossRefPubMed

33.

Batlevi CL, Kasamon Y, Bociek RG, Lee P, Gore L, Copeland A, Sorensen R, Ordentlich P, Cruickshank S, Kunkel L, Buglio D, Hernandez-Ilizaliturri F, Younes A (2016) ENGAGE- 501: phase II study of entinostat (SNDX-275) in relapsed and refractory hodgkin lymphoma. Haematologica 101:968–975. https://doi.org/10.3324/haematol.2016.142406CrossRefPubMedPubMedCentral

34.

Xiao D, Yue M, Su H, Ren P, Jiang J, Li F, Hu Y, Du H, Liu H, Qing G (2016) Polo-like kinase-1 regulates myc stabilization and activates a feedforward circuit promoting tumor cell survival. Mol Cell 64:493–506. https://doi.org/10.1016/j.molcel.2016.09.016CrossRefPubMed

35.

van Tilburg CM, Milde T, Witt R, Ecker J, Hielscher T, Seitz A, Schenk JP, Buhl JL, Riehl D, Fruhwald MC, Pekrun A, Rossig C, Wieland R, Flotho C, Kordes U, Gruhn B, Simon T, Linderkamp C, Sahm F, Taylor L, Freitag A, Burhenne J, Foerster KI, Meid AD, Pfister SM, Karapanagiotou-Schenkel I, Witt O (2019) Phase I/II intra-patient dose escalation study of vorinostat in children with relapsed solid tumor, lymphoma, or leukemia. Clin Epigenetics 11:188. https://doi.org/10.1186/s13148-019-0775-1CrossRefPubMedPubMedCentral

36.

Liu T, Guan F, Wang Y, Zhang Z, Li Y, Cui Y, Li Z, Liu H, Zhang Y, Wang Y, Ma S (2020) MS-275 combined with cisplatin exerts synergistic antitumor effects in human esophageal squamous cell carcinoma cells. Toxicol Appl Pharmacol 395:114971. https://doi.org/10.1016/j.taap.2020.114971CrossRefPubMed

37.

Holtrich U, Wolf G, Brauninger A, Karn T, Bohme B, Rubsamen-Waigmann H, Strebhardt K (1994) Induction and down-regulation of PLK, a human serine/threonine kinase expressed in proliferating cells and tumors. Proc Natl Acad Sci USA 91:1736–1740. https://doi.org/10.1073/pnas.91.5.1736CrossRefPubMedPubMedCentral

38.

Ren Y, Bi C, Zhao X, Lwin T, Wang C, Yuan J, Silva AS, Shah BD, Fang B, Li T, Koomen JM, Jiang H, Chavez JC, Pham LV, Sudalagunta PR, Wan L, Wang X, Dalton WS, Moscinski LC, Shain KH, Vose J, Cleveland JL, Sotomayor EM, Fu K, Tao J (2018) PLK1 stabilizes a MYC-dependent kinase network in aggressive B cell lymphomas. J Clin Invest 128:5517–5530. https://doi.org/10.1172/JCI122533CrossRefPubMedPubMedCentral

39.

Higuchi F, Fink AL, Kiyokawa J, Miller JJ, Koerner MVA, Cahill DP, Wakimoto H (2018) PLK1 inhibition targets myc-activated malignant glioma cells irrespective of mismatch repair deficiency-mediated acquired resistance to temozolomide. Mol Cancer Ther 17:2551–2563. https://doi.org/10.1158/1535-7163.MCT-18-0177CrossRefPubMedPubMedCentral

40.

Wang D, Veo B, Pierce A, Fosmire S, Madhavan K, Balakrishnan I, Donson A, Alimova I, Sullivan KD, Joshi M, Erlander M, Ridinger M, Foreman NK, Venkataraman S, Vibhakar R (2022) A novel PLK1 inhibitor onvansertib effectively sensitizes MYC-driven medulloblastoma to radiotherapy. Neuro Oncol 24:414–426. https://doi.org/10.1093/neuonc/noab207CrossRefPubMed

41.

Abbou S, Lanvers-Kaminsky C, Daudigeos-Dubus E, Laplace-Builhe LLED, Molenaar C, Vassal J, Geoerger G (2016) Polo-like kinase inhibitor volasertib exhibits antitumor activity and synergy with vincristine in pediatric malignancies. Anticancer Res 36:599–609PubMed

42.

Nguyen T, Parker R, Hawkins E, Holkova B, Yazbeck V, Kolluri A, Kmieciak M, Rahmani M, Grant S (2017) Synergistic interactions between PLK1 and HDAC inhibitors in non-hodgkin’s lymphoma cells occur in vitro and in vivo and proceed through multiple mechanisms. Oncotarget 8:31478–31493. https://doi.org/10.18632/oncotarget.15649CrossRefPubMedPubMedCentral

43.

Han Y, Lindner S, Bei Y, Garcia HD, Timme N, Althoff K, Odersky A, Schramm A, Lissat A, Künkele A, Deubzer HE, Eggert A, Schulte JH, Henssen AG (2019) Synergistic activity of BET inhibitor MK-8628 and PLK inhibitor volasertib in preclinical models of medulloblastoma. Cancer Lett 445:24–33. https://doi.org/10.1016/j.canlet.2018.12.012CrossRefPubMed

44.

Timme N, Han Y, Liu S, Yosief HO, García HD, Bei Y, Klironomos F, MacArthur IC, Szymansky A, von Stebut J, Bardinet V, Dohna C, Künkele A, Rolff J, Hundsdörfer P, Lissat A, Seifert G, Eggert A, Schulte JH, Zhang W, Henssen AG (2020) Small-molecule dual PLK1 and BRD4 inhibitors are active against preclinical models of pediatric solid tumors. Transl Oncol 13:221–232. https://doi.org/10.1016/j.tranon.2019.09.013CrossRefPubMed

45.

Olmos D, Barker D, Sharma R, Brunetto AT, Yap TA, Taegtmeyer AB, Barriuso J, Medani H, Degenhardt YY, Allred AJ, Smith DA, Murray SC, Lampkin TA, Dar MM, Wilson R, de Bono JS, Blagden SP (2011) Phase I study of GSK461364, a specific and competitive polo-like kinase 1 inhibitor, in patients with advanced solid malignancies. Clin Cancer Res 17:3420–3430. https://doi.org/10.1158/1078-0432.CCR-10-2946CrossRefPubMed

46.

Dong J, Park SY, Nguyen N, Ezhilarasan R, Martinez-Ledesma E, Wu S, Henry V, Piao Y, Tiao N, Brunell D, Stephan C, Verhaak R, Sulman E, Balasubramaniyan V, de Groot JF (2018) The polo-like kinase 1 inhibitor volasertib synergistically increases radiation efficacy in glioma stem cells. Oncotarget 9:10497–10509. https://doi.org/10.18632/oncotarget.24041CrossRefPubMedPubMedCentral

47.

Tandle AT, Kramp T, Kil WJ, Halthore A, Gehlhaus K, Shankavaram U, Tofilon PJ, Caplen NJ, Camphausen K (2013) Inhibition of polo-like kinase 1 in glioblastoma multiforme induces mitotic catastrophe and enhances radiosensitisation. Eur J Cancer 49:3020–3028. https://doi.org/10.1016/j.ejca.2013.05.013CrossRefPubMedPubMedCentral

48.

Robinson G, Parker M, Kranenburg TA, Lu C, Chen X, Ding L, Phoenix TN, Hedlund E, Wei L, Zhu X, Chalhoub N, Baker SJ, Huether R, Kriwacki R, Curley N, Thiruvenkatam R, Wang J, Wu G, Rusch M, Hong X, Becksfort J, Gupta P, Ma J, Easton J, Vadodaria B, Onar-Thomas A, Lin T, Li S, Pounds S, Paugh S, Zhao D, Kawauchi D, Roussel MF, Finkelstein D, Ellison DW, Lau CC, Bouffet E, Hassall T, Gururangan S, Cohn R, Fulton RS, Fulton LL, Dooling DJ, Ochoa K, Gajjar A, Mardis ER, Wilson RK, Downing JR, Zhang J, Gilbertson RJ (2012) Novel mutations target distinct subgroups of medulloblastoma. Nature 488:43–48. https://doi.org/10.1038/nature11213CrossRefPubMedPubMedCentral

Title: Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells
Authors: Gintvile Valinciute
Jonas Ecker
Florian Selt
Thomas Hielscher
Romain Sigaud
Johannes Ridinger
Venu Thatikonda
Charlotte Gatzweiler
Sarah Robinson
Julie Talbot
Flavia Bernardi
Daniel Picard
Mirjam Blattner-Johnson
Simone Schmid
David T. Jones
Cornelis M. van Tilburg
David Capper
Marcel Kool
Marc Remke
Ina Oehme
Stefan M. Pfister
Martine F. Roussel
Olivier Ayrault
Olaf Witt
Till Milde
Publication date: 15-05-2023
Publisher: Springer US
Keywords: Medulloblastoma
Medulloblastoma
Medulloblastoma
Published in: Journal of Neuro-Oncology / Issue 1/2023
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-023-04319-1

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Class I HDAC inhibitor entinostat synergizes with PLK1 inhibitors in MYC-amplified medulloblastoma cells

Abstract

Purpose

Methods

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Purpose

Methods

Results

Conclusion

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