[{"data":1,"prerenderedAt":-1},["ShallowReactive",2],{"doc-seo-383126-105":3,"detail-sidebar-cat-0-en-105":81,"doc-detail-383126-en":130},{"code":4,"msg":5,"data":6},0,"ok",{"site_id":7,"language":8,"slug":9,"title":10,"keywords":11,"description":12,"schema_data":13,"social_meta":74,"head_meta":76,"extra_data":78,"updated_unix":80},105,"en","microtubule-targeting-combined-with-hdac-inhibition-is-a-novel-therapeutic-strategy-for-diffuse-intrinsic-pontine-gliomas","Microtubule-Targeting Combined with HDAC Inhibition Is a Novel Therapeutic Strategy for Diffuse Intrinsic Pontine Gliomas","","Diffuse intrinsic pontine gliomas (DIPG) remain uniformly fatal childhood brain tumors lacking effective systemic therapy. A mutation in H3K27M drives loss of H3K27 methylation and widespread gene dysregulation. TRX-E-009–1 shows tumor-specific activity in DIPG neurosphere cultures, induces apoptosis, restores H3K27me3, and inhibits proliferation without activity in normal astrocytes. Combined treatment with the HDAC inhibitor SAHA extends survival in orthotopic models and further improves efficacy with irradiation.",{"@graph":14,"@context":73},[15,34,56],{"@type":16,"itemListElement":17},"BreadcrumbList",[18,23,27,31],{"item":19,"name":20,"@type":21,"position":22},"https://docshare.wps.com","Home","ListItem",1,{"item":24,"name":25,"@type":21,"position":26},"https://docshare.wps.com/document/","Document",2,{"item":28,"name":29,"@type":21,"position":30},"https://docshare.wps.com/document/healthcare/","Healthcare",3,{"item":32,"name":10,"@type":21,"position":33},"https://docshare.wps.com/document/microtubule-targeting-combined-with-hdac-inhibition-is-a-novel-therapeutic-strategy-for-diffuse-intrinsic-pontine-gliomas/383126/",4,{"url":32,"name":10,"@type":35,"image":36,"author":41,"headline":10,"publisher":44,"fileFormat":47,"inLanguage":8,"description":12,"dateModified":48,"datePublished":49,"encodingFormat":47,"isAccessibleForFree":50,"interactionStatistic":51},"DigitalDocument",{"url":37,"@type":38,"width":39,"height":40},"https://docshare.wps.com/thumbnails/microtubule-targeting-combined-with-hdac-inhibition-is-a-novel-therapeutic-strategy-for-diffuse-intrinsic-pontine-gliomas/383126.png","ImageObject",300,407,{"name":42,"@type":43},"Well Done","Person",{"url":19,"name":45,"@type":46},"DocShare","Organization","application/pdf","2026-10-30","2026-09-24",true,{"@type":52,"interactionType":53,"userInteractionCount":55},"InteractionCounter",{"@type":54},"ViewAction",8,{"@type":57,"mainEntity":58},"FAQPage",[59,65,69],{"name":60,"@type":61,"acceptedAnswer":62},"What challenge makes diffuse intrinsic pontine gliomas difficult to treat?","Question",{"text":63,"@type":64},"DIPG is an aggressive pediatric brainstem cancer that is uniformly fatal, and there are no established effective systemic therapies; focal irradiation remains standard. Its infiltrative growth and molecular dysregulation limit therapeutic response.","Answer",{"name":66,"@type":61,"acceptedAnswer":67},"How does TRX-E-009–1 affect DIPG cells?",{"text":68,"@type":64},"TRX-E-009–1 shows tumor-specific antitumor activity in DIPG neurosphere cultures, inhibits proliferation, induces apoptotic pathways, and increases cleaved caspase 3 and cleaved PARP. It also restores histone H3K27me3 methylation.",{"name":70,"@type":61,"acceptedAnswer":71},"Why does combining TRX-E-009–1 with HDAC inhibition improve outcomes?",{"text":72,"@type":64},"Co-administration with the HDAC inhibitor SAHA extends survival in DIPG orthotopic animal models, and the antitumor effect is further enhanced by irradiation. 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Vanniasinghe2, Anjana Gopalakrishnan2, Jie Liu2, Maria Tsoli1,2, and David S. Ziegler1,2,3  \n◥  \nDiffuse intrinsic pontine gliomas (DIPG) are an incurable childhood brain cancer for which novel treatments are needed. DIPGs are characterized by a mutation in the H3 histone (H3K27M), resulting in loss of H3K27 methylation and global gene dysregulation. TRXE-009–1 is a novel anticancer agent with preclinical activity demonstrated against a range of cancers. We examined the antitumor activity of TRX-E-009–1 against DIPG neurosphere cultures and observed tumor-specific activity with IC50s ranging from 20 to 100 nmol/L, whereas no activity was observed against normal  \nhuman astrocyte cells. TRX-E-009–1 exerted its anti-proliferative effect through the induction of apoptotic pathways, with marked increases in cleaved caspase 3 and cleaved PARP levels, while also restoring histone H3K27me3 methylation. Co-administration of TRX-E-009–1and the histone deacetylase(HDAC)inhibitorSAHA extended survival in DIPG orthotopic animal models. This antitumor effect was further enhanced with irradiation. Our findings indicate that TRX-E-009–1, combined with HDAC inhibition, represents a novel, potent therapy for children with DIPG.  \nIntroduction  \nDiffuse intrinsic pontine glioma (DIPG) is an aggressive brainstem tumor and the most common form of high-grade glioma in children, with amedian survival ofless than1year(1,2). DIPGis uniformly fatal and remains the leading cause of childhood brain tumor-related death (3) . There are no established systemic therapies, and focal irradiation remains the standard treatment (4, 5) . However, the application of autopsy and biopsy sampling has aided in understandingthe molecular landscape ofDIPG tumors over the past decade(6,7) . Approximately 80% of DIPG tumors harbor a mutation in the H3 histone (H3K27M), leading to loss of H3K27 trimethylation (H3K27me3) and aberrant gene expression (8) . Moreover, the development of patient-derived cultures and orthotopic models allows the preclinical testing of a variety of epigenetic, targeted agents, and immunotherapies (1, 9, 10) .  \nOne of the defining characteristics of DIPG tumors is the infiltrative and invasive growth patterns that contribute to limited therapeutic response (11). Tumor migration, cell division, and structural integrity depend upon microtubules composed of dynamic tubular polymers of a- and b-tubulin (12, 13) . Blocking the dynamics of microtubule assembly and disassembly results in disruption of cellular division,  \n1School of Clinical Medicine, UNSW Medicine & Health, UNSW Sydney, Sydney, NSW, Australia. 2Children’s Cancer Institute, Lowy Cancer Research Centre, UNSW Sydney, Kensington, NSW, Australia. 3Kids Cancer Centre, Sydney Children’s Hospital, High St, Randwick, Australia.  \nA. Ehteda and A. Khan contributed equally as first authors, and M. Tsoli and  \nD.S. Ziegler contributed equally as senior authors to this article.  \nCorresponding Author: David S. Ziegler, Kids Cancer Centre, Sydney Children’s Hospital, High St, Randwick 2031, Australia. E-mail: [d.ziegler@unsw.edu.au](d.ziegler@unsw.edu.au)[ ](d.ziegler@unsw.edu.au)[Mol Cancer Ther 2023](Mol Cancer Ther 2023);[22:1413](22:1413)–[21](21)  \n[doi:](doi: 10.1158/1535-7163.MCT-23-0179)[ 10.1158/1535-7163.MCT-23-0179](doi: 10.1158/1535-7163.MCT-23-0179)  \nThis open access article is distributed under the Creative Commons AttributionNonCommercial-NoDerivatives 4 . 0 International (CC BY-NC-ND 4 . 0) license.  \n􀀂2023The Authors;Published by the American Association for Cancer Research  \nmitotic arrest, and induction of apoptosis, thus making this a potential strategy for cancer therapy (14) . Trilexium (TRX-E-009–1) is a thirdgeneration benzopyran compound that can cross the blood–brain barrier (BBB) and reach bra","cbCaihQtzP1poyRz","https://ap.wps.com/l/cbCaihQtzP1poyRz","pdf",7475606,"English","# Introduction\n# Materials and Methods\n## Cell culture and reagents","[{\"question\":\"What challenge makes diffuse intrinsic pontine gliomas difficult to treat?\",\"answer\":\"DIPG is an aggressive pediatric brainstem cancer that is uniformly fatal, and there are no established effective systemic therapies; focal irradiation remains standard. Its infiltrative growth and molecular dysregulation limit therapeutic response.\"},{\"question\":\"How does TRX-E-009–1 affect DIPG cells?\",\"answer\":\"TRX-E-009–1 shows tumor-specific antitumor activity in DIPG neurosphere cultures, inhibits proliferation, induces apoptotic pathways, and increases cleaved caspase 3 and cleaved PARP. It also restores histone H3K27me3 methylation.\"},{\"question\":\"Why does combining TRX-E-009–1 with HDAC inhibition improve outcomes?\",\"answer\":\"Co-administration with the HDAC inhibitor SAHA extends survival in DIPG orthotopic animal models, and the antitumor effect is further enhanced by irradiation. The combination also drives anti-proliferative effects and promotes G2–M arrest and apoptosis.\"}]","Microtubule-Targeting Combined with HDAC Inhibition Is a Novel Therapeutic Strategy for Diffuse Intrinsic Pontine Gliomas | PDF",1790254382,23]