肝细胞癌疗法的最新发现策略

StephenW

Current discovery strategies for hepatocellular carcinoma therapeutics
Qiuzi Dai, Cunlong Zhang, Zigao Yuan, Qinsheng Sun & Yuyang Jiang
Pages 243-258 | Received 29 Jul 2019, Accepted 20 Nov 2019, Published online: 06 Dec 2019

    Download citation https://doi.org/10.1080/17460441.2020.1696769 CrossMark Logo CrossMark

ABSTRACT

Introduction: The global incidence of hepatocellular carcinoma (HCC) is not expected to decline significantly over the next 30 years. And although the latest gene sequencing studies have established its genetic map, the potentially targetable drivers of HCC are, so far, difficult to identify. To date, only seven drugs have been approved by the FDA for unresectable HCC treatment; thus, effective therapeutic breakthroughs are still needed urgently.

Areas covered: In this review, the authors discuss both genetic and epigenetic alterations in HCC and introduce the current progress with some of the representative molecular targeting inhibitors, listing some of the approved drugs for the targets of HCC. The structure–activity relationship of molecules (e.g. thalidomide, bortezomil) used for HCC is also discussed.

Expert opinion: Effective therapeutic targets and effective drugs for HCC treatment are an urgent unmet need. Better understanding and characterization of genetic and epigenetic alterations, which are important to hepatocarcinogenesis, may help to understand the molecular pathogenesis of HCC, as well as provide novel therapeutic lead compounds for HCC treatment.
KEYWORDS: Epigenetic, genetic, hepatocellular carcinoma, histone modification, receptor-tyrosine-kinase inhibitors, DNA methyltransferases
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Article highlights

    The global incidence of hepatocellular carcinoma (HCC) will not decline significantly over the next 30 years.

    Sorafenib was the first approved by FDA for the treatment of HCC. In the past 3 years, lenvatinib in the frontline, regorafenib, cabozantinib, and ramucirumab in the second line were approved by FDA. In addition, immunotherapy drugs, nivolumab, and pembrolizumab, which are monoclonal antibodies have been granted accelerated approval by FDA. By contrast, several kinase inhibitors (e.g. sunitinib, bevacizumab, and erlotinib) failed to improve survival in patients with unresectable HCC.

    Proof-of-concept and biomarker-based trials of molecularly targeted agents should be focus on signaling pathways of genetic and epigenetic alterations in HCC.

    Based on the urgent needs on clinical, the future research direction of liver cancer treatment is not only focused on the new drugs research, but also the multidisciplinary comprehensive treatment mode. Combined therapy including chemotherapy, targeted therapy, and immunotherapy would maximize the benefit of patients with HCC.

    All effective drugs in phase III trials of HCC were multi-kinase inhibitors with no known predictive biomarkers and the therapeutic effect of immune-checkpoint inhibitors also have no diagnostic tools. So, it is difficult to make sure the driving gene of HCC.

This box summarizes key points contained in the article.

StephenW

肝细胞癌疗法的最新发现策略
戴秋子，张存龙，袁自高，孙勤生，姜玉阳
第243-258页| 2019年7月29日接收，2019年11月20日接受，在线发布：2019年12月6日

    下载引文https://doi.org/10.1080/17460441.2020.1696769 CrossMark徽标CrossMark

抽象

简介：在未来30年中，预计全球肝细胞癌（HCC）发病率不会显着下降。而且，尽管最新的基因测序研究已经建立了其遗传图谱，但到目前为止，难以确定HCC的潜在可靶向驱动因素。迄今为止，FDA仅批准了7种药物用于不可切除的HCC治疗。因此，仍然迫切需要有效的治疗突破。

涵盖的领域：在这篇综述中，作者讨论了肝癌的遗传和表观遗传学改变，并介绍了一些代表性的分子靶向抑制剂的最新进展，列出了一些已批准的肝癌靶向药物。还讨论了用于HCC的分子（例如沙利度胺，硼替佐米）的构效关系。

专家意见：有效的治疗目标和有效的HCC治疗药物是亟待解决的问题。对肝癌发生非常重要的遗传和表观遗传学改变的更好理解和表征，可能有助于了解HCC的分子发病机理，并为HCC治疗提供新的治疗性先导化合物。
关键词：表观遗传，遗传，肝细胞癌，组蛋白修饰，受体酪氨酸激酶抑制剂，DNA甲基转移酶
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文章重点

    在接下来的30年中，全球肝细胞癌（HCC）的发病率不会显着下降。

    索拉非尼是FDA首次批准用于肝癌的治疗。在过去的3年中，前线的lenvatinib，二线的regorafenib，cabozantinib和ramucirumab已获FDA批准。此外，作为单克隆抗体的免疫疗法药物，尼古鲁单抗和派姆单抗也已获得FDA的加速批准。相比之下，几种激酶抑制剂（例如舒尼替尼，贝伐单抗和厄洛替尼）无法改善无法切除的HCC患者的生存率。

    分子靶向药物的概念验证和基于生物标志物的试验应侧重于HCC遗传和表观遗传改变的信号传导途径。

    基于临床的迫切需求，肝癌治疗的未来研究方向不仅集中在新药的研究上，而且还涉及多学科的综合治疗模式。包括化学疗法，靶向疗法和免疫疗法在内的综合疗法将使HCC患者的利益最大化。

    在HCC的III期临床试验中，所有有效药物均为多激酶抑制剂，尚无已知的预测生物标志物，免疫检查点抑制剂的治疗作用也没有诊断工具。因此，很难确定肝癌的驱动基因。

此框总结了文章中包含的关键点。