A synergistic interaction between HDAC‐ and PARP inhibitors in childhood tumors with chromothripsis

Khalid, Umar; Simović, Milena; Hammann, Linda A; Iskar, Murat; Wong, John; Kumar, R.; Jugold, Manfred; Sill, Martin; Bolkestein, Michiel; Kolb, Thorsten; Hergt, Michaela; Devens, Frauke; Ecker, Jonas; Kool, Marcel; Milde, Till; Westermann, Frank; Benner, Axel; Lewis, Joe; Dietrich, Sascha; Pfister, Stefan M.; Lichter, Peter; Zapatka, Marc; Ernst, Aurélie

doi:10.1002/ijc.34027

Cited by 7 publications

(2 citation statements)

References 34 publications

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“…The data provided here on a possible co-localization of MYC and PARP1 has not been previously described and warrants further investigation since it may provide further insight into a mechanistic interaction of both proteins. The factor of potential underlying BRCAness, as reported previously in primary group 3 MB samples, might also play a role in the observed sensitivity to PARPi [ 4 , 48 ].…”

Section: Discussionmentioning

confidence: 78%

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

Vollmer,

Ecker,

Hielscher

et al. 2023

J Neurooncol

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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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Section: Discussionmentioning

confidence: 78%

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

Vollmer,

Ecker,

Hielscher

et al. 2023

J Neurooncol

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“…Post-translational modifications such as DNA methylation, histone acetylation, histone methylation and poly(ADP-ribosyl) ation all have complex interactions and functional interplay. Several studies in IRD have highlighted these complex relationships, emphasising that epigenetic modifications do not take place in isolation (Nakao, 2001;Lee et al, 2006;Ummarino et al, 2021;Khalid et al, 2022;Miller et al, 2022). In 2010, Sancho-Pelluz and colleagues discovered that both HDAC and PARP were overactive in rd1 mice (Sancho-Pelluz et al, 2010).…”

Section: Interactions Between Different Posttranslational Modificationsmentioning

confidence: 99%

The role of epigenetic changes in the pathology and treatment of inherited retinal diseases

Miller

James

Harvey

et al. 2023

Front. Cell Dev. Biol.

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Elucidation of the cellular changes that occur in degenerating photoreceptors of people with inherited retinal diseases (IRDs) has been a focus for many research teams, leading to numerous theories on how these changes affect the cell death process. What is clearly emerging from these studies is that there are common denominators across multiple models of IRD, regardless of the underlying genetic mutation. These common markers could open avenues for broad neuroprotective therapeutics to prevent photoreceptor loss and preserve functional vision. In recent years, the role of epigenetic modifications contributing to the pathology of IRDs has been a particular point of interest, due to many studies noting changes in these epigenetic modifications, which coincide with photoreceptor cell death. This review will discuss the two broad categories of epigenetic changes, DNA methylation and histone modifications, that have received particular attention in IRD models. We will review the altered epigenetic regulatory events that are believed to contribute to cell death in IRDs and discuss the therapeutic potential of targeting these alterations.

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Epigenetic Priming and Development of New Combination Therapy Approaches

Meneceur

Grunewald

Niegisch

et al. 2023

Methods in Molecular Biology

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A synergistic interaction between HDAC‐ and PARP inhibitors in childhood tumors with chromothripsis

Cited by 7 publications

References 34 publications

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

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

The role of epigenetic changes in the pathology and treatment of inherited retinal diseases

Epigenetic Priming and Development of New Combination Therapy Approaches

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