Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG

Ehteda, Anahid; Simon, Sandy; Franshaw, Laura; Giorgi, Federico M.; Liu, Jie; Joshi, Swapna; Rouaen, Jourdin R.C.; Pang, Chi Nam Ignatius; Pandher, Ruby; Mayoh, Chelsea; Tang, Yujie; Khan, Aaminah; Ung, Caitlin; Tolhurst, Ornella; Kankean, Anne; Hayden, Elisha; Lehmann, Rebecca; Shen, Sylvie; Gopalakrishnan, Anjana; Trebilcock, Peter; Gurova, Katerina V.; Gudkov, Andrei V.; Norris, Murray D.; Haber, Michelle; Vittorio, Orazio; Tsoli, Maria; Ziegler, David S.

doi:10.1016/j.celrep.2021.108994

Cited by 27 publications

(21 citation statements)

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“…The FACT inhibitor, CBL0137, significantly decreased the survival of DIPG cells and impaired the growth of xenografts in mice as a single agent and synergized with panobinostat to cause these effects. In addition, CBL0137 increased trimethylation and acetylation of lysine 27 at H3, although the mechanism for this effect has not been explained (Ehteda et al, 2021). Moreover, the decrease in tumor sphere survival by CBL0137 was more pronounced in H3K27M-expressing DIPG spheres than in H3 wild-type human fibroblasts, normal human astrocytes, and H3K27 wild-type DIPG cells (Ehteda et al, 2021).…”

Section: Targeting Hdacs and Fact Complexmentioning

confidence: 97%

“…In addition, CBL0137 increased trimethylation and acetylation of lysine 27 at H3, although the mechanism for this effect has not been explained (Ehteda et al, 2021). Moreover, the decrease in tumor sphere survival by CBL0137 was more pronounced in H3K27M-expressing DIPG spheres than in H3 wild-type human fibroblasts, normal human astrocytes, and H3K27 wild-type DIPG cells (Ehteda et al, 2021). Overall, the FACT complex emerged as a promising target specifically in H3K27M-expressing pHGGs.…”

Section: Targeting Hdacs and Fact Complexmentioning

confidence: 99%

“…While H3K27M pHGGs have elevated levels of H3K27ac when compared to the tumors expressing the wild-type H3 variants, screening of various epigenetic modifying drugs showed that histone deacetylase (HDAC) inhibitors are among the most potent compounds decreasing the survival of pHGG cells (Grasso et al, 2015;Anastas et al, 2019). Several HDAC inhibitors were tested so far in pHGGs, including vorinostat, entinostat, and panobinostat (LBH589), with the latter showing the highest potency and being the most explored as a single agent or in combination with other drugs (see further sections) (Grasso et al, 2015;Nagaraja et al, 2017;Anastas et al, 2019;Krug et al, 2019;Lin et al, 2019;Ehteda et al, 2021;Vitanza et al, 2021). In addition, quisinostat and romidepsin emerged recently as potent HDAC inhibitors in treatment-naïve biopsyderived DMG models (Vitanza et al, 2021).…”

Section: Interfering With H3k27ac and Transcriptional Activity In H3k27m Phggsmentioning

confidence: 99%

“…A recent study showed that subunits of the FACT (facilitates chromatin transcription) complex, namely structure-specific recognition protein 1 (SSRP1) and suppressor of Ty16 (SPT16), are overexpressed in DIPG tumors when compared to normal brain tissues and normal human astrocytes (Ehteda et al, 2021). The FACT complex works as a histone chaperone interacting with nucleosomes and is involved in DNA repair, DNA replication, and transcription (Hsieh et al, 2013;Prendergast et al, 2020).…”

Section: Targeting Hdacs and Fact Complexmentioning

confidence: 99%

“…The FACT complex works as a histone chaperone interacting with nucleosomes and is involved in DNA repair, DNA replication, and transcription (Hsieh et al, 2013;Prendergast et al, 2020). Ehteda et al (2021) showed that the SSRP1 subunit of FACT directly interacts with the H3.3K27M mutant histone. The FACT inhibitor, CBL0137, significantly decreased the survival of DIPG cells and impaired the growth of xenografts in mice as a single agent and synergized with panobinostat to cause these effects.…”

Section: Targeting Hdacs and Fact Complexmentioning

confidence: 99%

See 4 more Smart Citations

Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas

et al. 2021

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Somatic mutations in histone encoding genes result in gross alterations in the epigenetic landscape. Diffuse intrinsic pontine glioma (DIPG) is a pediatric high-grade glioma (pHGG) and one of the most challenging cancers to treat, with only 1% surviving for 5 years. Due to the location in the brainstem, DIPGs are difficult to resect and rapidly turn into a fatal disease. Over 80% of DIPGs confer mutations in genes coding for histone 3 variants (H3.3 or H3.1/H3.2), with lysine to methionine substitution at position 27 (H3K27M). This results in a global decrease in H3K27 trimethylation, increased H3K27 acetylation, and widespread oncogenic changes in gene expression. Epigenetic modifying drugs emerge as promising candidates to treat DIPG, with histone deacetylase (HDAC) inhibitors taking the lead in preclinical and clinical studies. However, some data show the evolving resistance of DIPGs to the most studied HDAC inhibitor panobinostat and highlight the need to further investigate its mechanism of action. A new forceful line of research explores the simultaneous use of multiple inhibitors that could target epigenetically induced changes in DIPG chromatin and enhance the anticancer response of single agents. In this review, we summarize the therapeutic approaches against H3K27M-expressing pHGGs focused on targeting epigenetic dysregulation and highlight promising combinatorial drug treatments. We assessed the effectiveness of the epigenetic drugs that are already in clinical trials in pHGGs. The constantly expanding understanding of the epigenetic vulnerabilities of H3K27M-expressing pHGGs provides new tumor-specific targets, opens new possibilities of therapy, and gives hope to find a cure for this deadly disease.

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Section: Targeting Hdacs and Fact Complexmentioning

confidence: 97%

Section: Targeting Hdacs and Fact Complexmentioning

confidence: 99%

Section: Interfering With H3k27ac and Transcriptional Activity In H3k27m Phggsmentioning

confidence: 99%

Section: Targeting Hdacs and Fact Complexmentioning

confidence: 99%

Section: Targeting Hdacs and Fact Complexmentioning

confidence: 99%

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Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas

et al. 2021

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Brain‐Targeted Exosomes‐Based Drug Delivery System to Overcome the Treatment Bottleneck of Brainstem Glioma

Chen

Shan

Xia

et al. 2023

Adv Funct Materials

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Brain health is the humans’ primary goal in achieving health and longevity. Brainstem glioma (BSG) has a high disability and mortality rate, posing a serious threat to children's brain health. Delivery of drugs to the brainstem is limited by poor tumor targeting and low blood‐brain barrier (BBB) permeability. Thus, it is a great challenge to construct intracranial drug delivery systems with strong biocompatibility, low immunogenicity, and high BBB permeability for the delivery of drugs targeting BSG. Exosomes, as the next generation of novel delivery systems, have been widely used to across the BBB due to their advantages of good biocompatibility, stability, and permeability of the BBB and have made corresponding breakthroughs in targeted drug delivery for CNS diseases. This review summarizes natural, polypeptide functionalized, and physical methods‐assisted brain‐targeted exosomes‐based drug delivery systems, the drug treatment bottleneck of BSG, and highlights the potential of using a brain‐targeted exosomes‐based drug delivery system to overcome the drug treatment bottleneck of BSG. It provides new insights into using exosomes‐based drug delivery for BSG treatment.

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Cellular senescence in cancer: molecular mechanisms and therapeutic targets

Jin,

Duan,

et al. 2024

MedComm

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Aging exhibits several hallmarks in common with cancer, such as cellular senescence, dysbiosis, inflammation, genomic instability, and epigenetic changes. In recent decades, research into the role of cellular senescence on tumor progression has received widespread attention. While how senescence limits the course of cancer is well established, senescence has also been found to promote certain malignant phenotypes. The tumor‐promoting effect of senescence is mainly elicited by a senescence‐associated secretory phenotype, which facilitates the interaction of senescent tumor cells with their surroundings. Targeting senescent cells therefore offers a promising technique for cancer therapy. Drugs that pharmacologically restore the normal function of senescent cells or eliminate them would assist in reestablishing homeostasis of cell signaling. Here, we describe cell senescence, its occurrence, phenotype, and impact on tumor biology. A “one‐two‐punch” therapeutic strategy in which cancer cell senescence is first induced, followed by the use of senotherapeutics for eliminating the senescent cells is introduced. The advances in the application of senotherapeutics for targeting senescent cells to assist cancer treatment are outlined, with an emphasis on drug categories, and the strategies for their screening, design, and efficient targeting. This work will foster a thorough comprehension and encourage additional research within this field.

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Dual targeting of the epigenome via FACT complex and histone deacetylase is a potent treatment strategy for DIPG

Abstract: Highlights d CBL0137 inhibits DIPG tumor growth and restores H3K27me3 through FACT inhibition d Co-administration of CBL0137 and panobinostat enhances survival in DIPG xenografts d CBL0137 and panobinostat synergistically inhibit the Rb/ E2F1 pathway and restore H3K27me3

Cited by 27 publications

References 58 publications

Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas

Emerging Advances in Combinatorial Treatments of Epigenetically Altered Pediatric High-Grade H3K27M Gliomas

Brain‐Targeted Exosomes‐Based Drug Delivery System to Overcome the Treatment Bottleneck of Brainstem Glioma

Cellular senescence in cancer: molecular mechanisms and therapeutic targets

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