在肝癌表观遗传学的干扰：走出住所？

StephenW

Editorial
Interfering with epigenetics in hepatocellular carcinoma: Out of the shelter?

    Chris Verslype,

         doi:10.1016/j.jhep.2016.03.017
   
Refers To

        Michael Bitzer, Marius Horger, Edoardo G. Giannini, Tom M. Ganten, Marcus A. Wörns, Jens T. Siveke, Matthias M. Dollinger, Guido Gerken, Max E. Scheulen, Henning Wege, Vittorina Zagonel, Umberto Cillo, Franco Trevisani, Armando Santoro, Vincenzo Montesarchio, Nisar P. Malek, Julia Holzapfel, Thomas Herz, Astrid S. Ammendola, Stefano Pegoraro, Bernhard Hauns, et al.
        Resminostat plus sorafenib as second-line therapy of advanced hepatocellular carcinoma – The SHELTER study
        Journal of Hepatology, Volume 65, Issue 2, August 2016, Pages 280-288
            
Histone deacetylases (HDACs) regulate gene expression by enzymatic removal of the acetyl group from histones, making the DNA more compact and as such, silencing genes. At least 18 HDACs are known, and although the name refers to a histone substrate, the activity of HDACs is not limited to histones. They act also as acetyl-lysin removers on a variety of non-histone proteins with diverse biological functions (e.g., transcription factors p53, NF-κB and many others) [1].

In several cancers, including hepatocellular carcinoma (HCC), overexpression of individual HDACs has been shown to correlate with poor prognosis [2]. HDAC3 overexpression in HCC was significantly correlated with advanced tumor stage and early recurrence of HCC after surgery [3]. Moreover, HDAC3 was found to be selectively expressed in liver cancer stem cells (CSCs) and implicated in self-renewal of liver CSCs [3]. In contrast, some HDACs may exert a tumor suppressor role as liver-specific knockdown of HDAC3 resulted in overt HCC [4]. Especially persistent inactivation of the HDAC3/NCOR/SMRT axis may be detrimental, promoting the development of cancer by allowing the increase of histone acetylation during the S phase, leading to DNA damage [4]. HDACs may therefore not only serve as therapeutic targets in advanced cancer, but also act as tumor suppressors in developing tumors [5]. Inhibiting HDAC may lead to disruption of many pathways and may complicate a rational drug design.

A large number of HDAC inhibitors (HDACis) are of natural origin and present in garlic (allyl mercaptan), blueberries (piceatannol), broccoli (sulforaphane) and grapes (reversatrol) [6]. So far, three pan-HDAC inhibitors have been approved for the therapy of refractory cutaneous and peripheral T cell lymphoma (somidepsin, vorinostat and belinostat) [7] and others are under investigation for hematologic and solid cancers. The mode of action of this class of drugs seems to be related to apoptosis induction in tumor cells. The most common toxicities of HDACis are bone marrow suppression, fatigue and diarrhea [5]. In solid tumors, monotherapy with these agents has yielded insufficient responses.

The only phase I/II clinical trial so far using the HDAC inhibitor belinostat in patients with advanced HCC (62% first-line treatment), reported a disappointing median progression free survival (PFS) and overall survival (OS) of 2.64 and 6.6 months respectively [8].

In this issue of the Journal of Hepatology, Bitzer et al. report the results of the SHELTER study, a phase I/II clinical trial of resminostat, belonging to the same hydroxamic acid class of HDACis as belinostat [9]. Patients with advanced HCC and documented progression under treatment with sorafenib, were treated with resminostat, either alone or in combination with sorafenib. The combination treatment provided a PFS of 6.5 months and an OS of 8.1 months. In contrast, the results for the monotherapy group treated with resminostat were very poor. There were no unexpected or problematic safety issues. At first sight, the 8 months OS for resminostat and sorafenib may not seem exceptional, and comparable to the outcome of patients in the placebo arms of recent second-line trials [10]. However, the SHELTER investigators exclusively studied patients with documented sorafenib progression (and not sorafenib intolerance). There were no imbalances in the pattern of progression prior to entry in the study, that has recently been shown to be of prognostic importance and only a minority of patients was in the most favorable group [11].

Despite the moderate benefit and the non-randomized small nature of the study, this trial may revitalize the interest in HDAC inhibitors for advanced HCC. Treatment of sorafenib (with escalating doses) beyond progression has been previously evaluated and yielded no benefit [12]. The finding that resminostat may restore sensitivity to sorafenib represents the most important message from this trial. A future first-line phase III study may test the upfront combination of sorafenib and resminostat, vs. the addition to sorafenib of the HDAC inhibitor at the time of progression. Such a trial may also investigate the value of the transcription factor ZFP64, which has been suggested as a prognostic and predictive factor by the investigators of the SHELTER study.

To date, no established regimens exist for the treatment of patients with advanced HCC after failure of first-line treatment with the multikinase inhibitor sorafenib. While awaiting the results of the current phase III studies with cabozantinib, tivantinib, regorafinib and the promise of immunotherapy, we may now also consider the restoration of sensitivity to sorafenib by resminostat as a potential therapeutic option.
Conflict of interest

C. Verslype received research funding from Bayer, Pfizer, Ipsen, Sirtex and Novartis.
References

StephenW

社论
在肝癌表观遗传学的干扰：走出住所？

    克里斯Verslype，

         DOI：10.1016 / j.jhep.2016.03.017
   
指

        迈克尔·比泽尔，马吕斯Horger，爱德华多G.贾尼尼，汤姆·M. Ganten，马库斯A.沃恩斯，延T. Siveke，马蒂亚斯M.多林格，圭多Gerken，最大E. Scheulen，亨宁WEGE，Vittorina Zagonel，翁贝托Cillo，佛朗哥Trevisani阿曼多·桑托罗，文森佐蒙泰萨尔基奥，尼萨尔P.马利克，朱莉娅Holzapfel，托马斯·赫茨，阿斯特丽德S. Ammendola，斯特凡诺Pegoraro，伯恩哈德Hauns等。
        Resminostat加上索拉非尼作为晚期肝癌二线治疗药物 - 庇护研究
        中华肝脏病杂志，65卷，第2期，2016年8月，页280-288的
            
组蛋白脱乙酰酶（HDACs）通过酶促除去乙酰基从组蛋白调节基因表达，使得该DNA更紧凑，因此，沉默基因。至少18的HDAC是已知的，并且尽管名称是指一种组蛋白底物，HDAC的活性并不限定于组蛋白。它们还充当对各种非组蛋白具有不同的生物功能乙酰赖氨酸去除（例如，转录因子的p53，NF-κB和许多其他）[1]。

在数种癌症，包括肝细胞癌（HCC），从个人HDAC的表达已显示与不良预后[2]相关联。在HCC HDAC3过表达显著手术后与晚期肿瘤期和肝癌的早期复发相关[3]。此外，HDAC3被发现在肝癌干细胞（CSCs的）被选择性地表达，并且在肝的CSCs的自我更新牵连[3]。与此相反，一些的HDAC可施加一个抑癌作用HDAC3的肝特异性击倒导致明显的肝癌[4]。所述HDAC3的特别持久性失活/ NCOR / SMRT轴可能是有害的，通过使组蛋白乙酰化的过程中的S期的增加促进癌症的发展，导致DNA损伤[4]。的HDAC可能因此不仅可以作为治疗靶点在晚期癌症，但在显影肿瘤也充当肿瘤抑制[5]。抑制HDAC可能导致多种途径的破坏，可能一个合理的药物设计复杂化。

大量的HDAC抑制剂（HDACis）是天然起源和存在于大蒜（烯丙基硫醇），蓝莓（白皮杉醇），西兰花（莱菔硫烷）和葡萄（reversatrol）[6]。到目前为止，三泛HDAC抑制剂已被批准用于难治性皮肤和外周T细胞淋巴瘤（somidepsin，伏立诺他和belinostat）的治疗[7]等人正在接受调查的血液和固体癌症。这类药物的作用模式似乎在肿瘤细胞中是相关的细胞凋亡诱导。 HDACis的最常见的毒性是骨髓抑制，疲劳和腹泻[5]。在实体瘤，单用这些药物已经产生了反应不足。

唯一的I / II期临床试验迄今使用HDAC抑制剂belinostat在晚期肝癌患者（62％的一线治疗），报道了2.64和6.6个月令人失望的中位无进展生存期（PFS）和总生存期（OS）分别[8]。

在中华肝脏病杂志，比泽尔等人的这个问题。报告SHELTER研究的结果，相resminostat的I / II期临床试验中，属于同一羟肟酸类HDACis作为belinostat [9]。患者根据与索拉非尼治疗晚期HCC和记录进展，用resminostat处理，无论是单独使用或与索拉非尼组合。联合治疗提供了6.5个月的PFS和8.1个月的操作系统。相反，对于与resminostat治疗的单一疗法组的结果非常差。没有意外的或有问题的安全问题。乍一看，该8个月OS为resminostat和索拉非尼似乎也不例外，和媲美的患者在近期二线试验[10]的安慰剂组的结果。然而，研究者SHELTER专门研究了患者的记录索拉非尼的进展（而不是索拉非尼不耐受）。有在进展中的研究开始之前的图案中没有不平衡，最近已经被证明是预后重要性和仅少数患者在最有利的组[11]。

尽管温和益处和研究的非随机小的性质，该试验可以振兴为晚期HCC在HDAC抑制剂的兴趣。索拉非尼（不断升级的剂量）超越进展治疗先前已评估并没有产生任何益处[12]。这resminostat可以恢复敏感性索拉非尼的发现代表了该试验最重要的信息。未来的第一线III期临床研究可以测试索拉非尼和resminostat，主场迎战除了HDAC抑制剂索拉非尼在进展的时间的前期结合。这样的试验也可以调查转录因子ZFP64，这已被建议作为由暖棚研究的调查的预后和预测因子的值。

迄今为止，用于治疗患者的多激酶抑制剂索拉非尼一线治疗失败后晚期HCC存在没有既定方案。在等待与cabozantinib，tivantinib，regorafinib和免疫治疗的前景目前III期研究的结果，我们现在也考虑敏感性的索拉非尼由resminostat恢复作为一个潜在的治疗选择。
利益冲突

C. Verslype获得的研究经费来自拜耳，辉瑞，易普森，Sirtex和诺华。