靶向于受体酪氨酸激酶的胃癌分子靶向治疗

胃癌是一种常见的高死亡率的疾病,相当一部分患者确诊时已经处于晚期,失去手术时机,而胃癌对于细胞毒类抗肿瘤药物、放疗又不甚敏感。研究发现酪氨酸激酶的突变激活和/或过度表达可使细胞发生转变,在肿瘤形成中起重要的作用。本文主要对以酪氨酸激酶为靶点的生物靶向药物在胃癌治疗中的研究进展进行概述,主要可以归纳为三个方面:①以ErbB通道为靶点的靶向治疗;②以血管内皮生长因子(VEGF)及其受体通道为靶点的靶向治疗;③以其他受体如胰岛素样生长因子-1受体(IGF1R)为靶点的靶向治疗。     

Targeting receptor tyrosine kinases in gastric cancer

Molecularly targeted therapeutic agents are constantly being developed and have been shown to be effective in various clinical trials.One group of representative targeted oncogenic kinases,the receptor tyrosine kinases(RTKs),has been associated with gastric cancer development.Trastuzumab,an inhibitor of ERBB2,has been approved for the treatment of gastric cancer,although other receptor tyrosine kinases,such as epidermal growth factor receptor,vascular endothelial growth factor,platelet-derived growth factor receptor,c-Met,IGF-1R and fibroblast growth factor receptor 2,are also activated in gastric cancer.The promising results of the trastuzumab clinical trial for gastric cancer resulted in the approval of trastuzumab-based therapy as a first-line treatment for human epidermal growth factor receptor 2-positive patients.On the other hand,the trial examining bevacizumab in combination with conventional chemotherapy did not meet its primary goal of increasing the overall survival time of gastric cancer patients;however,a significantly higher response rate and a longer progression-free survival were observed in the bevacizumab arm of the trial.Other clinical trials,especially phaseⅢtrials that have tested drugs targeting RTKs,such as cetuximab,panitumumab,gefitinib,erlotinib,figitumumab,sorafenib,sunitinib and lapatinib,have shown that these drugs have modest effects against gastric cancer.This review summarizes the recent results from the clinical trials of molecularly targeted drugs and suggests that further improvements in the treatment of advanced gastric cancer can be achieved through the combination of conventional drugs with the new molecularly targeted therapies.     

ADAMTSL5 is an epigenetically activated gene underlying tumorigenesis and drug resistance in hepatocellular carcinoma

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Cancer-associated mutations in the p85α N-terminal SH2 domain activate a spectrum of receptor tyrosine kinases

The phosphoinositide 3-kinase regulatory subunit p85α is a key regulator of kinase signaling and is frequently mutated in cancers. In the present study, we showed that in addition to weakening the inhibitory interaction between p85α and p110α, a group of driver mutations in the p85α N-terminal SH2 domain activated EGFR, HER2, HER3, c-Met, and IGF-1R in a p110α-independent manner. Cancer cells expressing these mutations exhibited the activation of p110α and the AKT pathway. Interestingly, the activation of EGFR, HER2, and c-Met was attributed to the ability of driver mutations to inhibit HER3 ubiquitination and degradation. The resulting increase in HER3 protein levels promoted its heterodimerization with EGFR, HER2, and c-Met, as well as the allosteric activation of these dimerized partners; however, HER3 silencing abolished this transactivation. Accordingly, inhibitors of either AKT or the HER family reduced the oncogenicity of driver mutations. The combination of these inhibitors resulted in marked synergy. Taken together, our findings provide mechanistic insights and suggest therapeutic strategies targeting a class of recurrent p85α mutations.

PIK3R1, which encodes the p85α regulatory subunit of phosphoinositide 3-kinases (PI3Ks), is frequently mutated in cancers. PIK3R1 mutations are associated with poor survival of cancer patients [the Genomic Data Commons (GDC) Data Portal] (1). Cancer-associated mutations have been detected in all five protein domains of p85α, namely, the Src homology 3 (SH3) domain, GTPase-activating protein (GAP) domain, N-terminal SH2 (nSH2) domain, inter-SH2 (iSH2) domain, and C-terminal SH2 (cSH2) domain (2). Hotspot PIK3R1 mutations cluster in the iSH2 and SH2 domains in agreement with the primary roles of these domains in stabilizing and inhibiting p110 in the p85α–p110 heterodimer (3).The first reported and characterized clusters of cancer patient–derived mutations were located in two regions of the iSH2 domain (i.e., the E439–K459 and D560–W583 regions) (4–6). Driver mutations in these regions can disrupt the inhibitory interaction between the iSH2 and p110 C2 domains (7), thereby alleviating the inhibition of p110 kinase activity by p85α (8). The other driver mutations target the inhibitory interactions between the nSH2 domain and p110 helical domain (9). The nSH2 domain driver mutations (G376R and K379E) have been suggested to play oncogenic roles by weakening this inhibitory interface (4). Importantly, all these p85α mutants retain the ability to physically bind to p110 and stabilize it. The cSH2 domain interacts with the p110 kinase domain and contributes to p110 inhibition (10). A cSH2 domain driver mutation, K674R, elevates AKT phosphorylation (11). However, the effect of this mutant on p110 remains to be elucidated. Apart from binding to p110, the nSH2 and cSH2 domains bind to phosphotyrosine (pY)-containing consensus sequences (pYXXM) in pY-phosphorylated receptor tyrosine kinases (RTK) or adaptor proteins (3). Engineered p85α mutations in the nSH2 (R358A, S361D) and cSH2 (R649A, S652D) domains impair binding to pY peptides by either removing charge pairing (R358A and R649A) or introducing charge repulsion (S361D, S652D) to the pY phosphate group (12, 13). Binding to the pY motifs upon RTK stimulation is incompatible with the p110-inhibiting interactions of the p85α SH2 domains. Therefore, binding of p85α to pY motifs allows the controlled activation of p110.In this study, we revealed an oncogenic mechanism evoked by a group of driver mutations in the nSH2 domain. These p85α mutations promote the stabilization of the HER3 protein, thereby activating multiple RTKs. The activation of both RTKs and PI3K/AKT by these nSH2 domain driver mutations should be considered to achieve therapeutic efficacy.     

Role of liver resection in the management of multinodular hepatocellular carcinoma

Hepatocellular carcinoma (HCC) is the third leading cause of cancer related deaths worldwide. Various treatment modalities have been applied to HCC depending on the tumor load, functional capacity of the liver and the general condition of the patient. According to Barcelona Clinic Liver Cancer staging strategy and The American Association for the Study of Liver Disease guidelines, surgical resection is not advocated in the tretment of multinodular HCC. Despite this, many recent clinical studies show that, resection can achieve good results in patients with multinodular HCC and 5-year survival rate around 40% can be reached. If resection or transplantation is not performed, these patients are usually managed with palliative procedures such as transarterial chemoembolization, radioembolization and cytotoxic chemotherapy and 5-year survival of this group of patients will be extremely low. Although survival rates are lower and complications may be increased in this group of patients, liver resection can safely be performed in selected patients in experienced centers for the management of multinodular HCC.     

Loss of heterozygosity of the retinoblastoma gene in liver cirrhosis accompanying hepatocellular carcinoma

Carcinogenesis is a multistep process. Most hepatocellular carcinoma (HCC) is preceded by liver cirrhosis, but the genetic changes involved in cirrhosis are not known well. The present study was conducted to evaluate aberration of the retinoblastoma (RB) gene in HCC and adjacent non-tumorous liver using 22 patients with chronic liver damage accompanying HCC. The specimens obtained by microdissection from paraffinembedded tissues were analyzed using an assay based on the polymerase chain reaction for highly polymorphic nucleotide sequences of microsatellites in theRB gene. Out of 22 cases, 15 showed constitutional heterozygosity for the microsatellite markers. In 11 (73.3%) of these 15 informative cases, the primary HCC foci showed loss of heterozygosity (LOH). In 8 of these 11 doubly informative (informative and LOH-positive in primary HCC) cases, LOH was found in 20 (64.5%) of 31 microdissected non-tumorous foci. All of the non-tumorous foci showingRB loss were cirrhotic lesions but there were no foci of chronic hepatitis. The remaining 4 cases without LOH in HCC foci showed no LOH in non-tumorous lesions. In our study, LOH of theRB gene was frequently observed in liver cirrhosis surrounding tumor.Abbreviations RB retinoblastoma - HCC hepatocellular carcinoma - LOH loss of heterozygosity - PCR polymerase chain reaction - (CA) _n cytosine-adenine - (AT) _n adenine-thymine - n number of repeats     

Radiofrequency ablation of liver tumors: Actual limitations and potential solutions in the future

Over the past decade,radiofrequency ablation(RFA) has evolved into an important therapeutical tool for the treatment of non resectable primary and secondary liver tumors.The clinical benefit of RFA is represented in several clinical studies.They underline the safety and feasibility of this new and modern concept in treating liver tumors.RFA has proven its clinical impact not only in hepatocellular carcinoma(HCC) but also in metastatic disease such as colorectal cancer(CRC).Due to the increasing number of HCC and CRC,RFA might play an even more important role in the future.Therefore,the refinement of RFA technology is as important as the evaluation of data of prospective randomized trials that will help define guidelines for good clinical practice in RFA application in the future.The combination of hepatic resection and RFA extends the feasibility of open surgical procedures in patients with extensive tumors.Adverse effects of RFA such as biliary tract damage,liver failure and local recurrence remain an important task today but overall the long term results of RFA application in treating liver tumors are promising.Incomplete ablation of liver tumors due to insufficient technology of ablation needles,tissue cooling by the neighbouring blood vessels,large tumor masses and ablation of tumors in close vicinity to heat sensitive organs remain difficult tasks for RFA.Future solutions to overcome these limitations of RFA will include refinement of ultrasonographic guidance(accuracy of probe placement),improvements in needle technology(e.g.needles preventing charring)and intraductal cooling techniques.     

Synchronous development of HCC and CCC in the same subsegment of the liver in a patient with type C liver cirrhosis

As a result of having undergone computed tomography (CT), a 75-year-old woman with type-C liver cirrhosiswas shown to have two tumors on the ventral and dorsal sides of subsegment 3 (S3). The tumor on the ventral side was diagnosed as a classic hepatocellular carcinoma (HCC), while that on the dorsal side was considered atypical for a HCC. Although the indocyanine green (ICG) findings indicated poor hepatic reserve, the prothrombin time (PT) was relatively good. An operation was performed in February 2007; however, this resulted in exploratory laparotomy. Dynamic CT performed 12 mo after the operation revealed that the tumor on the dorsal side of S3 had apparently increased. The marginal portion of the tumor was shown to be in the early and parenchymal phases, while the internal portion was found to have grown only slightly in the delayed phase. We diagnosed this tumor as a cholangiocellular carcinoma (CCC). S3 subsegmentectomy was performed in April 2008. The tumor on the ventral side was pathologically diagnosed as a moderately differentiated HCC, and that on the dorsal side was diagnosed as a CCC. We can therefore report a rare case of synchronous development of HCC and CCC in the same subsegment of the liver in a patient with type-C liver cirrhosis. We also add a literature review for all the reported cases published in Japan and around the world, and summarize the features of double cancer exhibiting both HCC and CCC.     

骨髓间充质干细胞治疗肝脏疾病研究进展

骨髓间充质干细胞在适当的条件下可以分化为有功能的成熟肝细胞,为治疗终末期肝病提供了新思路。本文综述了骨髓间充质干细胞治疗肝硬化、肝细胞癌和肝衰竭等肝脏疾病的机制、临床应用价值、移植途径等方面的进展,介绍了在实际应用中存在的问题,并展望了该领域的应用前景。     

Intraductal papillary neoplasm of the bile duct in liver cirrhosis with hepatocellular carcinoma

A case of intraductal papillary neoplasm of the bile duct (IPNB) arising in a patient with hepatitis B-related liver cirrhosis with hepatocellular carcinoma (HCC) is reported. A 76-year-old man was admitted to our hospital with recurrent HCC. Laboratory data showed that levels of carcinoembryonic antigen and carbohydrate antigen 19-9 were elevated. He died of progressive hepatic failure. At autopsy,in addition to HCCs,an intraductal papillary proliferation of malignant cholangiocytes with fibrovascular core...     

表达HBVX基因的小鼠模型的建立及对肝细胞凋亡因子的影响

目的:探讨乙型肝炎病毒X(HBVX)基因及其产物对肝细胞凋亡相关基因表达的影响.方法:将实验用SPF级成年♂KM小鼠分为实验组、空质粒对照组、生理盐水对照组.实验组以构建好的PCDNA3.1-HBVX质粒,空质粒对照组以PCDNA3.1质粒,生理盐水对照组以生理盐水,通过尾静脉高压注入动物体内,在第48小时处死小鼠后,取肝组织,以RT-PCR,凝胶回收测序及Westernblot检测HBVX表达,以RT-PCR半定量检测小鼠肝组织内bax、c-myc及bcl-2的表达.结果:实验组RT-PCR显示465bp处有清楚条带,肝组织内有HBVXmRNA的存在,两对照组无HBVXmRNA存在,Western blot检测实验组有HBVX蛋白的表达;两对照组则无HBVX蛋白表达.通过对小鼠肝组织凋亡相关因子的半定量RT-PCR,相对于空质粒对照组和生理盐水对照组,转染HBVX基因的小鼠肝组织bax、c-myc及bcl-2的mRNA相对表达量明显增高,差异有显著性意义(bax:1.3127±0.0900vs1.0023±0.1670,0.9094±0.1081;c-myc:1.6294±0.0672vs1.2869±0....     

Detection of mutations in the insulin receptor gene in patients with insulin resistance by analysis of single-stranded conformational polymorphisms

Summary We analyzed single-stranded conformational poly morphisms to screen for mutations and polymorphisms in the insulin receptor gene in subjects with or without insulin resistance. Using this new technique, we demonstrated the existence of mutations in the insulin receptor gene which we had identified previously. In addition, a new mutation was found in exon 20 of the insulin receptor gene in a patient with moderate insulin resistance associated with morbid obesity, acanthosis nigricans, and polycystic ovary syndrome. The patient was heterozygous for a mutation substituting Leu (CTG) for Pro (CCG) at codon 1178. Pro¹¹⁷⁸ is a part of a characteristic sequence motif (D¹¹⁵⁰ F¹¹⁵¹ G¹¹⁵²-A¹¹⁷⁷ P¹¹⁷⁸ E¹¹⁷⁹) common to many protein kinases. Analysis of single-stranded conformational polymorphisms was also used to estimate the frequency of a polymorphism at codon 1058. The two codons CAC (1058 His) and CAT (1058 His) both had a prevalence of 50% in 30 Japanese subjects. These data demonstrate that analysis of single-stranded conformational polymorphisms is a simple and sensitive screening method for mutations and polymorphisms in the insulin receptor gene in subjects with or without insulin resistance. Identification of a mutation in the insulin receptor gene in a patient with a moderate degree of insulin resistance associated with morbid obesity suggests that insulin receptor mutations may exist in patients with Type 2 (non-insulin-dependent) diabetes mellitus associated with a moderate degree of insulin resistance.     

基于2018年版肝脏影像报告数据系统对比分析CT和MRI诊断肝细胞癌的效能

目的 比较CT和MRI按照2018年版肝脏影像报告数据系统(LI-RADS)诊断肝细胞癌(HCC)的效能.方法 2017年9月～2020年7月四川省肿瘤医院诊治的有HCC高危因素的72例患者(HCC 53例、非HCC恶性肿瘤10例、良性病变9例),接受CT和MRI检查.根据2018年版LI-RADS定义的影像学征象和分...     

吡格列酮对高脂饮食诱导的胰岛素抵抗大鼠肝组织蛋白酪氨酸磷酸酶-1B及胰岛素受体底物-2表达的影响

目的 观察毗格列酮对高脂饮食诱导的IR大鼠肝组织蛋白酪氨酸磷酸酶-1B（PTP-1B）及胰岛素受体底物-2（IRS-2）表达的影响。方法40只SD大鼠随机分为高脂饮食（HF）组30只和正常对照（Nc）组10只,其中HF组又分为高脂对照（HFN）亚组和毗格列酮（HFP）亚组,每组各15只。喂养12周后,HFP亚组给予吡格列酮灌胃2周,并测定大鼠体重、FPG、Fins、TG、TC、IS。应用免疫组化、免疫印迹、免疫沉淀技术检测肝组织PTP-1B及IRS-2的表达。结果免疫组化：HFN亚组PTP-1B表达较NC组增高（P〈0．01）,HFP亚组较HFN亚组降低（P〈0．01）;免疫印迹：HFN、HFP亚组PTP-1B表达均高于NC组（P〈0．01或P〈0．05）,且HFP亚组低于HFN亚组（P〈0．01）;免疫沉淀：HFN亚组IRS-2磷酸化程度较NC组降低（P〈0．01）,HFP亚组较HFN亚组增高（P〈0．05）。结论吡格列酮能够改善IR,其作用机制可能与抑制PTP-1B表达,从而使胰岛素信号转导分子IRS-2表达增强有关。     

评估免疫检查点抑制剂为基础的联合治疗在原发性肝癌患者中肝损伤发生情况的真实世界研究

目的:在原发性肝癌患者中评估以免疫检查点抑制剂为基础的联合治疗引起的肝功能损伤发生情况。方法:回顾性分析2018年1月1日至2021年3月31日在重庆医科大学附属第二医院感染病科住院,并接受程序性死亡蛋白其配体（PD-1/PD-L1）抗体治疗的65例原发性肝癌患者的临床资料。根据CTCAE V5.0标准评估治疗前后肝损...     

Defining the severity of liver dysfunction in patients with hepatocellular carcinoma by the model for end-stage liver disease-derived systems

Background

The model for end-stage liver disease (MELD) and serum sodium (Na) are important markers for liver functional reserve in patients with hepatocellular carcinoma. We aimed to determine the best model to define the severity of liver dysfunction in terms of outcome prediction among the 4 currently used systems (MELD, MELDNa, MELD-Na and ReFit MELDNa).

Methods

A total of 2308 prospectively enrolled patients with hepatocellular carcinoma were analysed. The prognostic ability was compared by the Akaike information criterion.

Results

MELDNa had the best prognostic accuracy overall, and for patients receiving curative and non-curative treatments, followed by MELD-Na, MELD and ReFit MELDNa. When patients were categorized into <8, 8–12, 12–16, 16–20 and >20, the adjusted risk ratios for MELDNa were 1.065 (p = 0.46), 0.996 (p = 0.973), 1.38 (p = 0.048) and 1.563 (p = 0.003) for the scores of 8–12, 12–16, 16–20 and >20, respectively, compared to the group with scores <8. The adjusted risk ratio for MELDNa was 1.014 (95% confidence interval, 1.001–1.027; p = 0.034) per unit score increment in the Cox model.

Conclusions

The MELDNa is the best marker to define the severity of liver dysfunction in hepatocellular carcinoma patients independent of treatment strategy. The ReFit MELDNa does not enhance the predictive accuracy of the MELD.     

Determinants of survival following hepatocellular carcinoma in Egyptian patients with untreated chronic HCV infection in the pre-DAA era

Background and Study Aims

In this study we assessed rates and determinants of survival in people with untreated chronic HCV infection and hepatocellular carcinoma (HCC) in an Egyptian liver clinic setting.