Combined Therapy of AXL and HDAC Inhibition Reverses Mesenchymal Transition in Diffuse Intrinsic Pontine Glioma

Meel, Michaël H.; Gooijer, Mark C. de; Metselaar, Dennis S.; Sewing, A.; Zwaan, Kenn; Waranecki, Piotr; Breur, Marjolein; Buil, Levi C.M.; Lagerweij, Tonny; Wedekind, Laurine E.; Twisk, Jos W. R.; Köster, Jan; Hashizume, Rintaro; Raabe, Eric H.; Carcaboso, Ángel M.; Bugiani, Marianna; Phoenix, Timothy N.; Tellingen, Olaf van; Vuurden, Dannis G. van; Kaspers, Gertjan J. L.; Hulleman, Esther

doi:10.1158/1078-0432.ccr-19-3538

Cited by 48 publications

(42 citation statements)

References 54 publications

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“…In the DKFZ-EP1NS model of EPN, SAHA induces neuronal differentiation associated with loss of stemness (Milde et al, 2011). As noted above, HDACi effects in H3K27M DIPG cells involve a decrease in stemness gene expression (Meel et al, 2020). These findings support the view that HDACis should be further investigated as prodifferentiating and stemness modulating agents in pediatric brain tumors.…”

Section: The Role Of Modulating Stemness and Differentiationsupporting

confidence: 65%

“…Combined treatment with the HDACi panobinostat and the AXL inhibitor BGB324 resulted in synergistic antitumor effects on DIPG cells, with reduced expression of genes related to mesenchymal phenotype, stemness, and DNA damage repair (Meel et al, 2020). HDACis also synergize with blockade of bromodomain inhibition or CDK7, which disrupts oncogenic transcription, in DIPG models.…”

Section: Diffuse Intrinsic Pontine Gliomamentioning

confidence: 98%

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Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Perla

Fratini

Cardoso

et al. 2020

Front. Cell Dev. Biol.

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Brain cancers are the leading cause of cancer-related deaths in children. Biological changes in these tumors likely include epigenetic deregulation during embryonal development of the nervous system. Histone acetylation is one of the most widely investigated epigenetic processes, and histone deacetylase inhibitors (HDACis) are increasingly important candidate treatments in many cancer types. Here, we review advances in our understanding of how HDACis display antitumor effects in experimental models of specific pediatric brain tumor types, i.e., medulloblastoma (MB), ependymoma (EPN), pediatric high-grade gliomas (HGGs), and rhabdoid and atypical teratoid/rhabdoid tumors (ATRTs). We also discuss clinical perspectives for the use of HDACis in the treatment of pediatric brain tumors.

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Section: The Role Of Modulating Stemness and Differentiationsupporting

confidence: 65%

Section: Diffuse Intrinsic Pontine Gliomamentioning

confidence: 98%

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Perla

Fratini

Cardoso

et al. 2020

Front. Cell Dev. Biol.

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“…Consistent with previous reports that evaluated broad-spectrum HDAC inhibitors 17,22,31,32 , panobinostat showed strong efficacy in vitro. However, CUDC-907, a dual-acting inhibitor of class I PI3K and HDAC 33 , had higher median AUC and was slightly more selective for pHGG models.…”

Section: High-throughput Screen For Drug Response Of Different Phgg Ssupporting

confidence: 91%

Patient-Derived Orthotopic Xenografts and Cell Lines from Pediatric High-Grade Glioma Recapitulate the Heterogeneity of Histopathology, Molecular Signatures, and Drug Response

Zhu

et al. 2020

Preprint

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Pediatric high-grade glioma (pHGG) is a major contributor to cancer-related death in children. In vitro and in vivo disease models reflecting the intimate connection between developmental context and pathogenesis of pHGG are essential to advance understanding and identify therapeutic vulnerabilities. We established 21 patient-derived pHGG orthotopic xenograft (PDOX) models and eight matched cell lines from diverse groups of pHGG. These models recapitulated histopathology, DNA methylation signatures, mutations and gene expression patterns of the patient tumors from which they were derived, and included rare subgroups not well-represented by existing models. We deployed 16 new and existing cell lines for high-throughput screening (HTS). In vitro HTS results predicted variable in vivo response to inhibitors of PI3K/mTOR and MEK signaling pathways. These unique new models and an online interactive data portal to enable exploration of associated detailed molecular characterization and HTS chemical sensitivity data provide a rich resource for pediatric brain tumor research.

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“…A more expansive in vitro followed by in vivo screen of the combinatorial druggable DMG landscape, with clinically relevant factors such as potency and blood–brain-barrier penetrance taken into account, revealed the proteasome inhibitor marizomib combined with panobinostat as the most promising pairing [ 88 ]. Additional in vivo studies have suggested inhibition of lysine demethylase [ 89 , 90 ], DNA methylation [ 63 ], AXL kinase [ 91 ], and PI3K [ 92 ] as promising combination strategies with panobinostat, several of which are now in clinical trials.…”

Section: Development Of Novel Therapiesmentioning

confidence: 99%

Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

Graham

Mellinghoff

2020

IJMS

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Pediatric high-grade glioma (pHGG) is the leading cause of cancer death in children. Despite histologic similarities, it has recently become apparent that this disease is molecularly distinct from its adult counterpart. Specific hallmark oncogenic histone mutations within pediatric malignant gliomas divide these tumors into subgroups with different neuroanatomic and chronologic predilections. In this review, we will summarize the characteristic molecular alterations of pediatric high-grade gliomas, with a focus on how preclinical models of these alterations have furthered our understanding of their oncogenicity as well as their potential impact on developing targeted therapies for this devastating disease.

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Combined Therapy of AXL and HDAC Inhibition Reverses Mesenchymal Transition in Diffuse Intrinsic Pontine Glioma

Cited by 48 publications

References 54 publications

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Histone Deacetylase Inhibitors in Pediatric Brain Cancers: Biological Activities and Therapeutic Potential

Patient-Derived Orthotopic Xenografts and Cell Lines from Pediatric High-Grade Glioma Recapitulate the Heterogeneity of Histopathology, Molecular Signatures, and Drug Response

Histone-Mutant Glioma: Molecular Mechanisms, Preclinical Models, and Implications for Therapy

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