肝癌的分子治疗

Molecular Therapy of Liver Cancer

摘要: 肝细胞癌(HCC)的全球负担正在增加，并可能年发病数很快超过100万例。基因组研究奠定了HCC分子生物学的基础；然而，最常见的突变是不可控的，只有约25%的肿瘤具有潜在的靶向驱动因素。尽管监测计划可导致40%~50%的患者早期诊断，但在潜在治疗可行的情况下，几乎一半的HCC患者最终接受了系统治疗。索拉非尼是第一个全身用药。一项标志性研究揭示了晚期HCC患者的治疗中位总生存期从8个月提高到11个月。新药——乐伐替尼、瑞格非尼、卡博替尼和雷莫芦单抗也已被证明改善临床结果，尽管总生存期中值仍为约1年；因此，治疗方面仍然需要突破。免疫检查点抑制剂现在被纳入HCC治疗药物和分子靶向疗法与免疫疗法的组合正在成为增强免疫反应的工具。对免疫疗法的反应或原发性耐药性的生物标志物的研究也在推进。在此，我们总结了分子靶点和HCC的治疗并讨论近期的进展，包括生物标志物驱动治疗和免疫治疗。

Abstract: The global burden of hepatocellular carcinoma (HCC) is increasing and may soon exceed 1 million annual cases. Genomic studies have laid the foundation of HCC molecular biology. However, the most common mutations are uncontrollable, and only about 25% of tumors have potential targeted drivers. Although surveillance programs can lead to early diagnosis in 40%~50% of patients, al-most half of HCC patients end up receiving systematic therapy where potential treatments are fea-sible. Sorafenib was the first systemic drug. A landmark study revealed that the median overall survival of patients with advanced HCC improved from 8 months to 11 months. The newer drugs—Levastinib, Regfinib, Cabotinib, and Ramolumab—have also been shown to improve clinical outcomes, although overall median survival is still about 1 year. So breakthroughs in treatment are still needed. Immune checkpoint inhibitors are now being incorporated into HCC therapeutics and combinations of molecular targeted therapies and immunotherapies are emerging as tools to en-hance immune response. Research on biomarkers of response to immunotherapy or primary drug resistance is also advancing. Here, we summarize molecular targets and therapies for HCC and dis-cuss recent advances, including biomarker-driven therapy and immunotherapy.