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Open Access 03-10-2023 | Medulloblastoma | Research

Class I HDAC inhibition reduces DNA damage repair capacity of MYC-amplified medulloblastoma cells

Authors: Johanna Vollmer, Jonas Ecker, Thomas Hielscher, Gintvile Valinciute, Johannes Ridinger, Nora Jamaladdin, Heike Peterziel, Cornelis M. van Tilburg, Ina Oehme, Olaf Witt, Till Milde

Published in: Journal of Neuro-Oncology | Issue 3/2023

Abstract

Purpose

MYC-driven Group 3 medulloblastoma (MB) (subtype II) is a highly aggressive childhood brain tumor. Sensitivity of MYC-driven MB to class I histone deacetylase inhibitors (HDACi) has been previously demonstrated in vitro and in vivo. In this study we characterize the transcriptional effects of class I HDACi in MYC-driven MB and explore beneficial drug combinations.

Methods

MYC-amplified Group 3 MB cells (HD-MB03) were treated with class I HDACi entinostat. Changes in the gene expression profile were quantified on a microarray. Bioinformatic assessment led to the identification of pathways affected by entinostat treatment. Five drugs interfering with these pathways (olaparib, idasanutlin, ribociclib, selinexor, vinblastine) were tested for synergy with entinostat in WST-8 metabolic activity assays in a 5 × 5 combination matrix design. Synergy was validated in cell count and flow cytometry experiments. The effect of entinostat and olaparib on DNA damage was evaluated by γH2A.X quantification in immunoblotting, fluorescence microscopy and flow cytometry.

Results

Entinostat treatment changed the expression of genes involved in 22 pathways, including downregulation of DNA damage response. The PARP1 inhibitors olaparib and pamiparib showed synergy with entinostat selectively in MYC-amplified MB cells, leading to increased cell death, decreased viability and increased formation of double strand breaks, as well as increased sensitivity to additional induction of DNA damage by doxorubicin. Non-MYC-amplified MB cells and normal human fibroblasts were not susceptible to this triple treatment.

Conclusion

Our study identifies the combination of entinostat with olaparib as a new potential therapeutic approach for MYC-driven Group 3 MB.

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Ostrom QT et al (2019) CBTRUS statistical report: primary brain and other central nervous system tumors diagnosed in the United States in 2012–2016. Neuro Oncol. https://doi.org/10.1093/neuonc/noz150CrossRefPubMedPubMedCentral

Gajjar A et al (2021) Outcomes by clinical and molecular features in children with medulloblastoma treated with risk-adapted therapy: results of an international phase III trial (SJMB03). J Clin Oncol 39(7):822–835PubMedPubMedCentralCrossRef

Michalski JM et al (2021) Children’s oncology group phase III trial of reduced-dose and reduced-volume radiotherapy with chemotherapy for newly diagnosed average-risk medulloblastoma. J Clin Oncol 39(24):2685–2697PubMedPubMedCentralCrossRef

Northcott PA et al (2017) The whole-genome landscape of medulloblastoma subtypes. Nature 547(7663):311–317PubMedPubMedCentralCrossRef

Schwalbe EC et al (2017) Novel molecular subgroups for clinical classification and outcome prediction in childhood medulloblastoma: a cohort study. Lancet Oncol 18(7):958–971PubMedPubMedCentralCrossRef

Ecker J et al (2015) Targeting class I histone deacetylase 2 in MYC amplified group 3 medulloblastoma. Acta Neuropathol Commun 3:22PubMedPubMedCentralCrossRef

Ecker J, Witt O, Milde T (2013) Targeting of histone deacetylases in brain tumors. CNS oncology 2(4):359–376PubMedPubMedCentralCrossRef

Pei Y et al (2016) HDAC and PI3K antagonists cooperate to inhibit growth of MYC-driven medulloblastoma. Cancer Cell 29(3):311–323PubMedPubMedCentralCrossRef

Ecker J et al (2021) Reduced chromatin binding of MYC is a key effect of HDAC inhibition in MYC amplified medulloblastoma. Neuro Oncol 23(2):226–239PubMedCrossRef

10.

Bondarev AD et al (2021) Recent developments of HDAC inhibitors: Emerging indications and novel molecules. Br J Clin Pharmacol 87(12):4577–4597PubMedCrossRef

11.

Morel D et al (2020) Combining epigenetic drugs with other therapies for solid tumours—past lessons and future promise. Nat Rev Clin Oncol 17(2):91–107PubMedCrossRef

12.

Connolly RM et al (2021) E2112: Randomized phase III trial of endocrine therapy plus entinostat or placebo in hormone receptor-positive advanced breast cancer a trial of the ECOG-ACRIN cancer research group. J Clin Oncol 39(28):3171–3181PubMedPubMedCentralCrossRef

13.

Zagni C et al (2017) The search for potent, small-molecule HDACIs in cancer treatment: a decade after vorinostat. Med Res Rev 37(6):1373–1428PubMedCrossRef

14.

Milde T et al (2012) HD-MB03 is a novel Group 3 medulloblastoma model demonstrating sensitivity to histone deacetylase inhibitor treatment. J Neurooncol 110(3):335–348PubMedCrossRef

15.

Rettig I et al (2015) Selective inhibition of HDAC8 decreases neuroblastoma growth in vitro and in vivo and enhances retinoic acid-mediated differentiation. Cell Death Dis 6(2):e1657PubMedPubMedCentralCrossRef

16.

Team, R.C., R: A language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria. https://www.R-project.org/. 2019.

17.

Merico D et al (2010) Enrichment map: a network-based method for gene-set enrichment visualization and interpretation. PLoS ONE 5(11):e13984PubMedPubMedCentralCrossRef

18.

Krämer A et al (2014) Causal analysis approaches in Ingenuity Pathway Analysis. Bioinformatics 30(4):523–530PubMedCrossRef

19.

Peterziel H et al (2022) Drug sensitivity profiling of 3D tumor tissue cultures in the pediatric precision oncology program INFORM. NPJ Precis Oncol 6(1):94PubMedPubMedCentralCrossRef

20.

Milde T et al (2011) A novel human high-risk ependymoma stem cell model reveals the differentiation-inducing potential of the histone deacetylase inhibitor Vorinostat. Acta Neuropathol 122(5):637–650PubMedPubMedCentralCrossRef

21.

Mäkelä P, Zhang SM, Rudd S (2021) Drug synergy scoring using minimal dose response matrices. BMC Res Notes. https://doi.org/10.1186/s13104-021-05445-7CrossRefPubMedPubMedCentral

22.

Huang X et al (2004) Assessment of histone H2AX phosphorylation induced by DNA topoisomerase I and II inhibitors topotecan and mitoxantrone and by the DNA cross-linking agent cisplatin. Cytometry A 58(2):99–110PubMedCrossRef

23.

Archer TC et al (2018) Proteomics, post-translational modifications, and integrative analyses reveal molecular heterogeneity within medulloblastoma subgroups. Cancer Cell. https://doi.org/10.1016/j.ccell.2018.08.004CrossRefPubMedPubMedCentral

24.

Kanehisa M (2019) Toward understanding the origin and evolution of cellular organisms. Protein Sci 28(11):1947–1951PubMedPubMedCentralCrossRef

25.

Gene Ontology C (2021) The Gene Ontology resource: enriching a GOld mine. Nucleic Acids Res 49(D1):D325–D334CrossRef

26.

Fabregat A et al (2018) Reactome graph database: Efficient access to complex pathway data. PLoS Comput Biol 14(1):e1005968PubMedPubMedCentralCrossRef

27.

Gupta M et al (2019) The Blood-Brain Barrier (BBB) score. J Med Chem 62(21):9824–9836PubMedCrossRef

28.

Xiong Y et al (2020) Pamiparib is a potent and selective PARP inhibitor with unique potential for the treatment of brain tumor. Neoplasia 22(9):431–440PubMedPubMedCentralCrossRef

29.

Wang S et al (2019) Uncoupling of PARP1 trapping and inhibition using selective PARP1 degradation. Nat Chem Biol 15(12):1223–1231PubMedPubMedCentralCrossRef

30.

Murai J et al (2012) Trapping of PARP1 and PARP2 by clinical PARP inhibitors. Cancer Res 72(21):5588–5599PubMedPubMedCentralCrossRef

31.

Ray Chaudhuri A, Nussenzweig A (2017) The multifaceted roles of PARP1 in DNA repair and chromatin remodelling. Nat Rev Mol Cell Biol 18:610PubMedPubMedCentralCrossRef

32.

Perez-Fidalgo JA et al (2019) GEICO1601-ROLANDO: a multicentric single arm Phase II clinical trial to evaluate the combination of olaparib and pegylated liposomal doxorubicin for platinum-resistant ovarian cancer. Future Sci OA. https://doi.org/10.4155/fsoa-2018-0107CrossRefPubMedPubMedCentral

33.

Zhang B et al (2020) Class I histone deacetylase inhibition is synthetic lethal with BRCA1 deficiency in breast cancer cells. Acta Pharmaceutica Sinica B 10(4):615–627PubMedCrossRef

34.

Lahue RS, Frizzell A (2012) Histone deacetylase complexes as caretakers of genome stability. Epigenetics 7(8):806–810PubMedPubMedCentralCrossRef

35.

Sun T et al (2019) Histone deacetylase inhibition up-regulates MHC class I to facilitate cytotoxic T lymphocyte-mediated tumor cell killing in glioma cells. J Cancer 10(23):5638–5645PubMedPubMedCentralCrossRef

36.

Hazini A, Fisher K, Seymour L (2021) Deregulation of HLA-I in cancer and its central importance for immunotherapy. J Immunother Cancer. https://doi.org/10.1136/jitc-2021-002899CrossRefPubMedPubMedCentral

37.

Vlot AHC et al (2019) Applying synergy metrics to combination screening data: agreements, disagreements and pitfalls. Drug Discov Today 24(12):2286–2298PubMedCrossRef

38.

Pascal JM (2018) The comings and goings of PARP-1 in response to DNA damage. DNA Repair (Amst) 71:177–182PubMedCrossRef

39.

Gupta VG et al (2021) Entinostat, a selective HDAC1/2 inhibitor, potentiates the effects of olaparib in homologous recombination proficient ovarian cancer. Gynecol Oncol 162(1):163–172PubMedPubMedCentralCrossRef

40.

Rasmussen RD et al (2016) Enhanced efficacy of combined HDAC and PARP targeting in glioblastoma. Mol Oncol 10(5):751–763PubMedPubMedCentralCrossRef

41.

Ha K et al (2014) Histone deacetylase inhibitor treatment induces “BRCAness” and synergistic lethality with PARP inhibitor and cisplatin against human triple negative breast cancer cells. Oncotarget 5(14):5637–5650PubMedPubMedCentralCrossRef

42.

Marijon H et al (2018) Co-targeting poly(ADP-ribose) polymerase (PARP) and histone deacetylase (HDAC) in triple-negative breast cancer: Higher synergism in BRCA mutated cells. Biomed Pharmacother 99:543–551PubMedCrossRef

43.

van Vuurden DG et al (2011) PARP inhibition sensitizes childhood high grade glioma, medulloblastoma and ependymoma to radiation. Oncotarget 2(12):984–996PubMedPubMedCentralCrossRef

44.

Ning J-F et al (2019) Myc targeted CDK18 promotes ATR and homologous recombination to mediate PARP inhibitor resistance in glioblastoma. Nat Commun 10(1):2910–2910PubMedPubMedCentralCrossRef

45.

Di Giulio S et al (2021) A combination of PARP and CHK1 inhibitors efficiently antagonizes MYCN-driven tumors. Oncogene 40:6143PubMedPubMedCentralCrossRef

46.

Colicchia V et al (2017) PARP inhibitors enhance replication stress and cause mitotic catastrophe in MYCN-dependent neuroblastoma. Oncogene 36(33):4682–4691PubMedCrossRef

47.

Caracciolo D et al (2021) Exploiting MYC-induced PARPness to target genomic instability in multiple myeloma. Haematologica 106(1):185–195PubMedCrossRef

48.

Khalid U et al (2022) A synergistic interaction between HDAC- and PARP inhibitors in childhood tumors with chromothripsis. Int J Cancer 151(4):590–606PubMedCrossRef

49.

Del Conte G et al (2014) Phase I study of olaparib in combination with liposomal doxorubicin in patients with advanced solid tumours. Br J Cancer 111(4):651–659PubMedPubMedCentralCrossRef

50.

Boussios S et al (2019) Combined strategies with poly (ADP-Ribose) Polymerase (PARP) inhibitors for the treatment of ovarian cancer: a literature review. Diagnostics (Basel, Switzerland) 9(3):87PubMed

Title: Class I HDAC inhibition reduces DNA damage repair capacity of MYC-amplified medulloblastoma cells
Authors: Johanna Vollmer
Jonas Ecker
Thomas Hielscher
Gintvile Valinciute
Johannes Ridinger
Nora Jamaladdin
Heike Peterziel
Cornelis M. van Tilburg
Ina Oehme
Olaf Witt
Till Milde
Publication date: 03-10-2023
Publisher: Springer US
Keywords: Medulloblastoma
Medulloblastoma
Medulloblastoma
Published in: Journal of Neuro-Oncology / Issue 3/2023
Print ISSN: 0167-594X
Electronic ISSN: 1573-7373
DOI: https://doi.org/10.1007/s11060-023-04445-w

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Class I HDAC inhibition reduces DNA damage repair capacity of 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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