Molecular targeted drugs, comprehensive classification and preclinical models for the implementation of precision immune oncology in hepatocellular carcinoma.
Molecular targeted drugs, comprehensive classification and preclinical models for the implementation of precision immune oncology in hepatocellular carcinoma.
复制标题
分子靶向药物、综合分类和临床前模型，用于在肝细胞癌中实施精准免疫肿瘤学。
DOI：
10.1007/s10147-022-02174-0
复制
发表时间：
2022
影响因子：
3.3
通讯作者：
Tanaka S.
中科院分区：
文献类型：
--
作者：
Shimada S;Tanaka S.
肝细胞癌（HCC）是一种复杂的异质性疾病，具有较高的发病率和死亡率。分子靶向药物包括多激酶抑制剂和免疫检查点抑制剂的最新进展已经证明晚期HCC患者的生存率显著提高，但发现精确区分应答者和非应答者的替代标志物仍然是一个具有挑战性的问题。基于基因组的医学已经将癌症治疗从经验性地使用细胞毒性剂改变为在各种类型的癌症中理论上使用分子靶向药物，而在HCC中由于缺乏可药用靶点而没有改变。综合基因组学和转录组学分析显示，HCC可分为增殖型、CTNNB1突变型和代谢性疾病相关型3种主要亚型，具有不同的分子和免疫学特征，越来越多的研究利用临床数据和临床前模型证明了亚型与分子靶向药物反应之间的密切相关性。数十种免疫活性小鼠模型，如流体动力学尾静脉注射模型和植入式同基因模型，反映了亚型的分子特征和肿瘤免疫微环境，有助于我们评估单一和联合治疗的疗效，并了解其易感性和耐药性的分子机制。因此，共识分类和相关的临床前模型可以加速预测生物标志物的建立和亚型特异性治疗的发展。
Hepatocellular carcinoma (HCC) is a complex heterogeneous disease with high morbidity and mortality. Recent progress in molecular targeted drugs including multikinase inhibitors and immune checkpoint inhibitors has demonstrated substantial survival improvement in patients with advanced HCC, but it remains as a challenging issue to discover surrogate markers for precisely distinguishing responders and non-responders. Genome-based medicine has changed cancer treatment from empirical use of cytotoxic agents to theoretical use of molecular targeted drugs in various types of cancer, while not in HCC due to lack of druggable targets. Integrated genomic and transcriptomic analysis reveal that HCC is divided into three major subtypes, proliferative,CTNNB1-mutated and metabolic disease-associated, with distinctive molecular and immunological features, and an increasing number of studies provide evidence for the close correlation between the subtype and the response to molecular targeted drugs using both of clinical data and preclinical models. Dozens of immunocompetent mouse models, such as hydrodynamic tail vain injection models and implantable syngeneic models, reflect molecular characteristics and tumor immune microenvironment of the subtypes, and help us to evaluate the efficacy of single and combination therapies and understand the molecular mechanisms underlying vulnerability and resistance to them. Thus, the consensus classification and relevant preclinical models could accelerate the establishment of predictive biomarkers and the development of subtype-specific therapies.