弥漫性中线神经胶质瘤(DMG)是中枢神经系统的侵袭性且致命的儿科肿瘤,对治疗具有高度抵抗力。组蛋白H3(H3-K27M)上残基27的赖氨酸替换为甲硫氨酸是DMG中的驱动突变,重塑这些细胞的表观遗传景观以促进肿瘤发生。H3-K27M胶质瘤的特征是组蛋白乙酰化和甲基化途径的失调,以及致癌MYC途径。为了寻找有效的治疗方法,我们研究了组蛋白脱乙酰酶(HDACs)和MYC双重靶向治疗这些肿瘤的潜力.用Sulfopin治疗H3-K27M患者来源的细胞,一种显示在体内阻断MYC驱动的肿瘤的抑制剂,与HDAC抑制剂伏立诺他联合使用,导致细胞活力大幅下降。此外,转录组和表观基因组谱分析揭示了这种药物组合在显著的致癌途径如mTOR的下调中的协同作用。最后,患者来源的原位异种移植模型的体内研究显示,在用该药物组合治疗的小鼠中,肿瘤生长显著减少.这些结果突出了PIN1和HDAC抑制剂的联合治疗作为这些侵袭性肿瘤的有希望的治疗方法。
弥漫性中线神经胶质瘤(DMGs)是儿童中最具侵袭性和致命性的脑癌。它们通常与组蛋白的变化有关,控制基因活性并赋予染色体结构的蛋白质。大多数患有DMGs的儿童,例如,它们的组蛋白H3蛋白具有相同的异常(称为H3-K27M突变)。这种变化影响了称为甲基和乙酰基的小化学标签如何添加到组蛋白3上,这反过来改变了蛋白质打开和关闭基因的方式。因此,肿瘤开始发展。一种针对DMGs的潜在治疗策略是使用组蛋白去乙酰化酶抑制剂(HDACi),一种有前途的药物,可以抑制从组蛋白中去除乙酰基的酶。患者可以对HDACi产生耐药性,然而,强调需要探索其他方法。一种可能性是用几种药物治疗患者,每个通常针对一个独特的生物过程,有助于癌症的出现。这种联合方法可以有多种好处;药物可能会放大彼此的作用,例如,并且细胞在当时对一种以上的化合物产生抗性的可能性也较小。此外,联合用药中的每种药物都可以较低的剂量使用,以减少副作用并使患者受益。DMG肿瘤细胞通常具有较高的称为MYC的蛋白质活性水平,这可能有助于肿瘤的生长。Algranati,Oren等人。因此,开始测试将HDACi称为Vorinostat与阻断MYC活性的药物(Sulfopin)联合使用是否可以作为这种癌症的有效治疗方法。8名DMG患者的肿瘤样本接受了单独的Sulfopin治疗,或与伏立诺他联合使用的磺福平。暴露于两种药物的细胞不太可能存活,和额外的遗传实验表明,联合治疗导致促进肿瘤发展的途径被阻断。当将磺胺嘧啶和伏立诺他都施用于生长人类DMG肿瘤的小鼠时,动物表现出肿瘤生长的更大减少。DMG的治疗选择通常有限,化疗通常无效,手术不可能。Algranati的作品,Oren等人。提示将HDACi和靶向MYC途径的药物联合使用是一种策略,应进一步研究以确定是否可能临床应用.
Diffuse midline gliomas (DMGs) are aggressive and fatal pediatric tumors of the central nervous system that are highly resistant to treatments. Lysine to methionine substitution of residue 27 on histone H3 (H3-K27M) is a driver mutation in DMGs, reshaping the epigenetic landscape of these cells to promote tumorigenesis. H3-K27M gliomas are characterized by deregulation of histone acetylation and methylation pathways, as well as the oncogenic MYC pathway. In search of effective treatment, we examined the therapeutic potential of dual targeting of histone deacetylases (HDACs) and MYC in these tumors. Treatment of H3-K27M patient-derived cells with Sulfopin, an inhibitor shown to block MYC-driven tumors in vivo, in combination with the HDAC inhibitor Vorinostat, resulted in substantial decrease in cell viability. Moreover, transcriptome and epigenome profiling revealed synergistic effect of this drug combination in downregulation of prominent oncogenic pathways such as mTOR. Finally, in vivo studies of patient-derived orthotopic xenograft models showed significant tumor growth reduction in mice treated with the drug combination. These results highlight the combined treatment with PIN1 and HDAC inhibitors as a promising therapeutic approach for these aggressive tumors.
Diffuse midline gliomas (DMGs) are among the most aggressive and fatal brain cancers in children. They are often associated with changes in histones, the proteins that control gene activity and give chromosomes their structure. Most children with DMGs, for example, share the same anomaly in their histone H3 protein (referred to as the H3-K27M mutation). This change affects how small chemical tags called methyl and acetyl groups can be added onto histone 3, which in turn alters the way the protein can switch genes on and off. As a result, tumours start to develop. One potential therapeutic strategy against DMGs is to use histone deacetylase inhibitors (HDACi), a promising type of drugs which inhibits the enzymes that remove acetyl groups from histones. Patients can develop resistance to HDACi, however, highlighting the need to explore other approaches. One possibility is to treat patients with several types of drugs, each usually targeting a distinct biological process that contributes to the emergence of cancer. This combined approach can have multiple benefits; the drugs potentially amplify each other’s effect, for example, and it is also less likely for cells to become resistant to more than one compound at the time. In addition, each drug in the combination can be used in a lower dose to reduce side effects and benefit patients. DMG tumour cells often feature higher activity levels of a protein known as MYC, which can contribute to the growth of the tumour. Algranati, Oren et al. therefore set out to test whether combining an HDACi known as Vorinostat with a drug that blocks MYC activity (Sulfopin) can act as an effective treatment for this cancer. Tumour samples from eight DMG patients were treated with either Sulfopin alone, or Sulfopin in association with Vorinostat. Cells exposed to both drugs were less likely to survive, and additional genetic experiments showed that the combined treatment had resulted in pathways that promote tumour development being blocked. When both Sulfopin and Vorinostat were administered to mice made to grow human DMG tumors, the animals showed a greater reduction in tumor growth. Treatment options for DMG are usually limited, with chemotherapy often being ineffective and surgery impossible. The work by Algranati, Oren et al. suggests that combining HDACi and drugs targeting the MYC pathway is a strategy that should be examined further to determine whether clinical applications are possible.