Emerging Therapies for Hepatocellular Carcinoma (HCC).
Emerging Therapies for Hepatocellular Carcinoma (HCC).
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肝细胞癌（HCC）的新兴疗法。
作者：
原发性肝癌，也称为肝细胞癌（HCC），被认为是全球主要的健康挑战。由于早期无症状阶段的诊断延迟，HCC 会达到严重的侵袭阶段，从而对患者的生存产生显着的负面影响。此外，HCC 对传统癌症治疗（例如化疗和放疗）表现出明显的抵抗力。各种新的和先进的疗法正在不断得到评估，以获得 HCC 治疗的突破，从而提高总体生存率和无复发生存率。适当识别和选择靶基因以及采用安全有效的治疗方法（例如基因治疗或免疫治疗）是有效治疗 HCC 的关键策略。本综述旨在就新兴方法作为更有效、更安全的 HCC 治疗途径提供视角。肝细胞癌（HCC）起源于肝细胞，占原发性肝癌的 90%。根据 2020 年全球癌症发病率、死亡率和患病率 (GLOBOCAN)，肝癌是全球第六大常见癌症，也是癌症相关死亡的第三大常见原因。 HCC 预后仍然不佳的原因是 HCC 早期无症状，导致诊断较晚，并且对传统化疗和放疗具有明显抵抗力。肝移植是早期的首选治疗方法，而手术切除、射频消融 (RFA) 和经动脉化疗栓塞 (TACE) 是美国食品和药物管理局 (FDA) 批准的晚期 HCC 治疗方法。晚期 HCC 的其他一线治疗包括广谱酪氨酸激酶抑制剂 (TKI)，如索拉非尼和乐伐替尼，以及免疫疗法和抗血管生成疗法的组合，即阿特珠单抗和贝伐珠单抗。然而，这些策略名义上延长了生存曲线，导致广谱毒副作用，并且患者最终产生治疗耐药性。 HCC 中的一些常见突变，例如端粒酶逆转录酶 (TERT)、连环蛋白 β 1 (CTNNB1) 和肿瘤蛋白 p53 (TP53) 基因的突变，仍然被认为是无法成药的。在这种情况下，确定适当的基因靶标和特定的基因递送方法为安全有效地治疗 HCC 创造了基于基因和免疫的疗法的潜力。本文重点阐述了 HCC 治疗的现状，重点介绍了潜在的基因靶点和先进技术，如溶瘤病毒载体、纳米粒子、嵌合抗原受体 (CAR)-T 细胞、免疫治疗和成簇规则间隔短回文重复序列/CRISPR 相关蛋白 9 (CRISPR/Cas9)，并描述了 HCC 治疗的未来前景。
Primary liver cancer, also known as Hepatocellular carcinoma (HCC), is considered to be a major global health challenge. Due to delays in diagnosis at early asymptomatic stages, HCC reaches a severe aggressive stage, thereby having a significant negative impact on patient survival. In addition, HCC shows marked resistance to conventional cancer treatments such as chemo- and radiotherapy. A variety of new and advanced therapies are continuously being evaluated to acquire a breakthrough in HCC treatment to enhance overall and recurrence-free survival. Appropriate identification and selection of target genes and utilization of safe and effective therapeutic approaches, such as gene therapy or immunotherapy, are key strategies for the effective treatment for HCC. This review paper intends to provide a perspective on emerging approaches as avenues towards more effective and safer therapies for HCC. Hepatocellular carcinoma (HCC) arises from hepatocytes and accounts for 90% of primary liver cancer. According to Global Cancer Incidence, Mortality and Prevalence (GLOBOCAN) 2020, globally HCC is the sixth most common cancer and the third most common cause of cancer-related deaths. Reasons for HCC prognosis remaining dismal are that HCC is asymptomatic in its early stages, leading to late diagnosis, and it is markedly resistant to conventional chemo- and radiotherapy. Liver transplantation is the treatment of choice in early stages, while surgical resection, radiofrequency ablation (RFA) and trans arterial chemoembolization (TACE) are Food and Drug Administration (FDA)-approved treatments for advanced HCC. Additional first line therapy for advanced HCC includes broad-spectrum tyrosine kinase inhibitors (TKIs), such as sorafenib and lenvatinib, as well as a combination of immunotherapy and anti-angiogenesis therapy, namely atezolizumab and bevacizumab. However, these strategies provide nominal extension in the survival curve, cause broad spectrum toxic side effects, and patients eventually develop therapy resistance. Some common mutations in HCC, such as in telomerase reverse transcriptase (TERT), catenin beta 1 (CTNNB1) and tumor protein p53 (TP53) genes, are still considered to be undruggable. In this context, identification of appropriate gene targets and specific gene delivery approaches create the potential of gene- and immune-based therapies for the safe and effective treatment of HCC. This review elaborates on the current status of HCC treatment by focusing on potential gene targets and advanced techniques, such as oncolytic viral vectors, nanoparticles, chimeric antigen receptor (CAR)-T cells, immunotherapy, and clustered regularly interspaced short palindromic repeats/CRISPR-associated protein 9 (CRISPR/Cas9), and describes future prospects in HCC treatment.
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