Highly expressed Claudin18.2 as a potential therapeutic target in advanced gastric signet-ring cell carcinoma (SRCC)

BackgroundAdvanced gastric signet-ring cell carcinoma (SRCC) is a specific type of malignant gastric cancer (GC) with distinct poorer survival. Claudin18.2 (CLDN18.2) is a promising neo-biomarker for the treatment of GC. Clinical trials of CLDN18.2-targeted antibody and T cell-based immunotherapy providing promising prospects for the treatment of GC. The effect of antibody therapy depended on the expression rate of CLDN18.2 has been found in clinical trials. This study aimed to determine the prevalence and the therapeutic value of CLDN18.2 in advanced gastric SRCC.MethodsExpression of CLDN18.2 in 105 formalin-fixed, paraffin-embedded (FFPE) tumor tissues was detected by immunohistochemistry (IHC) and evaluated according to FAST criteria. Next-generation sequencing (NGS) using 416 pan-cancer genes panel was performed to characterize the genomic landscape in 61 advanced gastric SRCC patients. Fisher’s exact test was used to determine gene differences in different CLDN18.2 expression levels.ResultsA total number of 105 advanced gastric SRCC samples were analyzed, of which 95.2% (100/105) were positive stained. Moderate-to-strong CLDN18.2 expression was observed in 64.8% (68/105) of all samples. In particularly, 21.0% (22/105) samples had positive staining in more than 90% tumor cells. No significance was found between CLDN18.2 expression and overall survival (OS). NGS results showed that single nucleotide variations (SNVs) could be frequently found in TP53 (26.2%), CDH1 (19.7%), MED12 (18.0%), PKHD1 (18.0%) and ARID1A (11.5%), besides, copy number variations (CNVs) were rich in NOTCH1 (18.0%) and FLT4 (9.8%) in SRCC samples. Moreover, SNVs in GRIN2A was found in 20% of the patients who had CLDN18.2 staining in <40% of tumor cells (P=0.043), indicating CLDN18.2 expression might be related to the aberration of GRIN2A in advanced gastric SRCC.ConclusionsThe highly expressed CLDN18.2 among advanced gastric SRCC patients that we found certified the value of CLDN18.2-targeted therapy in this specific type of GC. In addition, Analyses between CLDN18.2 expression and genetic abnormalities provided novel therapeutic options for advanced gastric SRCC.     

CLDN18.2在胃癌中的研究进展

CLDN18.2是表达于正常胃黏膜的紧密连接蛋白，参与构成细胞间的紧密连接，影响细胞旁离子通透性。CLDN18.2在胃癌中阳性率可达40%左右，其表达特异性使其成为胃癌治疗的潜在靶点。靶向CLDN18.2的抗体药IMAB362联合化疗可显著延长CLDN18.2阳性胃癌患者生存，IMAB362有望进入胃癌一线治疗。然而由于检测抗体研发瓶颈，截止目前有关CLDN18.2研究有限，此外由于CLDN18.2临床试验处于初始阶段，目前研究结果尚不明了，关于CLDN18.2阳性胃癌的认识仍缺乏整体观。本文对CLDN18.2相关的既往研究及进展进行综述，以期整合CLDN18.2相关进展，为CLDN18.2阳性胃癌临床及转化研究提供参考，并为其未来发展方向提供可能的思路。      

抗EGFR家族靶向药物在胃癌治疗中的研究进展

胃癌发病率占全球癌症发病率的第4位,死亡率占第2位。大多数胃癌患者就诊时已属中晚期,失去手术机会,化疗及分子靶向治疗作为胃癌治疗的有效手段,越来越受到临床研究及实践的重视。近年来,抗表皮生长因子受体（EGFR）家族靶向治疗在胃癌治疗中取得了丰硕的成果。本文总结了EGFR家族信号转导机制及相关靶向药物在胃癌治疗中的研究进展。     

CLDN18.2蛋白在恶性肿瘤治疗中的研究进展

随着分子生物学研究的进展，靶向治疗已成为除手术、放疗、化疗之外恶性肿瘤治疗中的第四种有效手段。与传统化疗药物不同，分子靶向治疗药物具有特异性强、疗效明显、不良反应较小等优点。CLDN18.2蛋白是新发现的一种跨膜蛋白，具有高选择性特点，稳定地过表达于多种恶性肿瘤中，尤其是消化系统肿瘤及其转移瘤。近年来，其特异性抗体claudiximab（zolbetuximab/ IMAB362）在最新的临床试验中取得了显著的成功，CLDN18.2蛋白有望成为某些特定恶性肿瘤靶向治疗的分子靶点。      

胃癌常见生物标记物及相应靶向治疗的研究进展

由于胃癌早期症状不明显和胃镜常规检查普及不足等原因,我国约80%胃癌患者就诊时已到晚期。目前,临床上胃癌治疗手段有限,单纯手术治疗的生存率仅在20%左右。由于放化疗未能明显提高患者生存率且毒副反应较大,因此,临床上急需一种新型的治疗手段来改善胃癌高发病率和高死亡率的现状。当下流行的靶向治疗,就是以相关生物标记物为靶点的一类低毒、高效的治疗方式。目前,临床试验中显示出相关性的靶向治疗生物标记物有人表皮生长因子受体2(Human epidermal growth factor receptor 2,HER2)、血管内皮细胞生长因子(Vascular endothelial growth factor, VEGF)、密蛋白-18剪接变体2(Dense protein-18 splice variant 2,Claudin 18.2)及间质-上皮细胞转化因子(Mesenchymal epithelial transition factor, MET)等,其中HER2的靶向抑制剂曲妥珠单抗是第一个被批准用于胃癌治疗的分子靶向药物,MET扩增已被证实是胃癌的不良预后因素。此外,由于近年来高通量测序...     

胃恶性肿瘤靶向治疗与免疫检查点治疗的新进展

近年来，胃恶性肿瘤的靶向治疗与免疫检查点治疗取得积极进展。靶向治疗药物的研究及应用取得突破，向着精准化方向迈进；免疫检查点治疗在胃恶性肿瘤中也展现了巨大的潜力，已有多个免疫检查点抑制剂陆续获批上市，此外多项新药临床试验也正在进行中。将实验室研究成果尽快转化为临床试验研究仍是我们努力的方向。     

A multicentre,phase IIa study of zolbetuximab as a single agent in patients with recurrent or refractory advanced adenocarcinoma of the stomach or lower oesophagus: the MONO study

BackgroundClaudin 18.2 (CLDN18.2) is physiologically confined to gastric mucosa tight junctions; however, upon malignant transformation, perturbations in cell polarity lead to CLDN18.2 epitopes being exposed on the cancer cell surface. The first-in-class monoclonal antibody, zolbetuximab (formerly known as IMAB362), binds to CLDN18.2 and can induce immune-mediated lysis of CLDN18.2-positive cells.Patients and methodsPatients with advanced gastric, gastro-oesophageal junction (GEJ) or oesophageal adenocarcinomas with moderate-to-strong CLDN18.2 expression in ≥50% of tumour cells received zolbetuximab intravenously every 2 weeks for five planned infusions. At least three patients were enrolled in two sequential cohorts (cohort 1300 mg/m²; cohort 2600 mg/m²); additional patients were enrolled into a dose-expansion cohort (cohort 3600 mg/m²). The primary end point was the objective response rate [ORR: complete and partial response (PR)]; secondary end points included clinical benefit [ORR+stable disease (SD)], progression-free survival, safety/tolerability, and zolbetuximab pharmacokinetic profile.ResultsFrom September 2010 to September 2012, 54 patients were enrolled (cohort 1, n = 4; cohort 2, n = 6; cohort 3, n = 44). Three patients in cohort 1 and 25 patients in cohorts 2/3 received at least 5 infusions. Antitumour activity data were available for 43 patients, of whom 4 achieved PR (ORR 9%) and 6 (14%) had SD for a clinical benefit rate of 23%. In a subgroup of patients with moderate-to-high CLDN18.2 expression in ≥70% of tumour cells, ORR was 14% (n = 4/29). Treatment-related adverse events occurred in 81.5% (n = 44/54) patients; nausea (61%), vomiting (50%), and fatigue (22%) were the most frequent.ConclusionsZolbetuximab monotherapy was well tolerated and exhibited antitumour activity in patients with CLDN18.2-positive advanced gastric or GEJ adenocarcinomas, with response rates similar to those reported for single-agent targeted agents in gastric/GEJ cancer trials.ClinicalTrials.gov numberNCT01197885.     

基于MUC1为靶点的乳腺癌治疗研究进展北大核心

黏蛋白1(mucin 1,MUC1)是黏蛋白家族中最容易被识别的跨膜蛋白,在乳腺癌细胞中过度表达且糖基化水平明显降低,并在乳腺癌发生发展中起到至关重要的作用。作为乳腺癌的治疗靶点,MUC1多年来受到广泛的研究,并已经取得了显著成效。目前,以MUC1为靶点的乳腺癌的治疗研究主要包括基于配体靶向治疗、免疫疗法及一体化诊疗。本文对近年来基于MUC1基因为靶点的乳腺癌治疗研究进展情况进行综述。     

晚期胃癌治疗的研究进展

目前,晚期胃癌的主要治疗手段仍以化疗为主,但其效果并不让人满意,近年来,出现了新的化疗药物及化疗方案,如三氟吡啶/替普拉西酯、FLOT化疗方案等。随着肿瘤分子生物学的不断深入,越来越多的靶向药物在胃癌的治疗中被证明有效,如VEGFR-2抑制剂阿帕替尼、抗VEGFR-2抗体雷莫芦单抗、酪氨酸激酶抑制剂阿法替尼等。免疫治疗也是胃癌综合治疗的热点之一,主要为免疫检查点抑制剂,包括程序性细胞死亡受体1检查点抑制剂纳武单抗、派姆单抗等。新药物的出现给晚期胃癌的治疗带来了新的机遇,本文将对目前晚期胃癌的化疗、靶向治疗、免疫治疗等研究进展进行综述。     

胃癌免疫检查点抑制剂作用机制及最新研究进展

胃癌治疗有限,预后较差。目前肿瘤免疫治疗因其显著的生存获益已成为除手术、化疗、放疗及靶向治疗之外有效的新型肿瘤治疗手段。免疫检查点抑制剂作为肿瘤免疫治疗的之一,已被批准用于多种肿瘤的治疗,提示胃癌免疫治疗时代已经到来。本文介绍了免疫治疗中免疫检查点抑制剂的作用机制及相关研究进展。     

The Functions of MicroRNAs and Their Potential Applications in the Diagnosis and Treatment of Gastric Cancer

Gastric cancer is a highly malignant disease with complex pathogenic mechanisms, and has high incidence and mortality rate. At present, the diagnosis of gastric cancer mainly includes gastroscopy, serum analysis and needle biopsy, and the treatment methods include conventional surgical resection, radiotherapy and chemotherapy. Yet, some limitations were involved in these diagnostic and therapeutic methods, so accurate targeted therapy has received considerable attention. MicroRNAs (miRNAs) are non-coding RNA that can interact with the 3-terminal non-translational region of the target gene mRNA to reduce the expression of the target gene, participate in the regulation of multiple signaling pathways, and play an important role in life activities of the cell. More and more studies have shown that miRNAs can participate in the formation and development of cancer, and many abnormally expressed miRNAs in gastric cancer cells are considered to be potential targets for clinical diagnosis and treatment of gastric cancer. This paper summarizes research progress of miRNAs in gastric cancer, and aims to provide new ideas for the diagnosis and treatment of gastric cancer.     

HER-2阴性胃癌的分子靶向治疗

目前分子靶向治疗已成为胃癌研究领域的热点。人类表皮生长因子受体-2（HER-2）靶基因的发现及相关靶向治疗已在临床广泛应用,而 HER-2阳性的发病人群＜20％。除 HER-2外,针对肿瘤细胞生长、浸润及血管生成等的靶点和靶向治疗值得关注。一些分子靶向药物应用于临床并呈现良好的疗效,为 HER-2阴性胃癌患者带来希望。     

TFF3作为肿瘤生物标志物的研究

三叶因子3（trefoil factor 3, TFF3）为三叶因子多肽家族成员之一,与肿瘤的发生发展密切相关,可促进肿瘤的侵袭、转移与血管生成。作为肿瘤生物标志物,TFF3对胃癌诊断具有较高的敏感度和特异性,优于胃蛋白酶原（Pepsinogen, PG）标志物,是胃癌非侵入性筛查潜在的理想标志物,并可应用于胃肠道肿瘤化疗药效与预后的评价,同时,TFF3应用于子宫内膜样腺癌及甲状腺微小浸润性滤泡癌的病理诊断也具有重大临床价值。TFF3作为新型肿瘤生物标志物,在肿瘤分子诊断与靶向、个体化治疗领域倍受临床关注。     

弥漫型胃癌免疫治疗的现状及研究进展

免疫治疗通过激活机体自身的免疫系统对肿瘤进行攻击,是当前肿瘤治疗的热点,已在包括胃癌在内的多种恶性肿瘤中获得亮眼的成果。实体瘤由于其局部的免疫抑制性微环境为免疫治疗带来了挑战。弥漫型胃癌是胃癌中预后较差的亚型,对现有的化疗及靶向药物均不敏感,迫切需要探索新的疗法来解决这一难题。现有的研究发现,弥漫型胃癌相较于肠型胃癌具有更独特的免疫微环境。免疫治疗能否成为改善弥漫型胃癌患者预后的新治疗策略值得探究。本文重点关注了弥漫型胃癌的肿瘤微环境和免疫治疗的现状,并探讨了未来免疫治疗应用于弥漫型胃癌可能的发展方向。      

胃癌Her-2的表达与靶向治疗

胃癌在的全球范围内的发病率居癌症第四位,致死率居癌症第二位。标准的化学治疗方案在延长胃癌生存时间方面发挥了重要的作用。但由于多数胃癌在确诊时已处在进展期,因此当前的医学实践只能满足有限的治疗选择。在过去几十年中,关于胃癌发生的分子机制的研究不断获得新进展。通过靶向抑制人类表皮生长因子受体2（Her-2）来治疗进展期胃癌,为患者提供了新的治疗方案。曲妥珠单抗,是一种Her-2单克隆抗体,是第一种治疗转移性胃癌的靶向药物,它与以顺铂及5-氟尿嘧啶为基础的化学治疗的联合应用,可以使胃癌整体生存获益。而Her-2过度表达为靶向治疗提供了证据。因此,本文就近年来关于胃癌Her-2过度表达和胃癌的靶向治疗做一综述。     

进展期胃癌的分子靶向治疗进展

胃癌是目前世界上危害人类健康的主要疾病之一,不能手术切除的进展期胃癌预后较差,寻求手术以外途径治疗胃癌的转移、复发具有重要意义。分子靶向治疗具有分子特异性和选择性,能高效并选择性地抑制或杀伤肿瘤细胞,同时减少对人体正常组织的损伤,是目前肿瘤治疗领域发展的新方向。随着胃癌分子病理学的研究深入,针对进展期胃癌的分子靶向治疗的药物研发成功并开始走向临床。本文综合近年来较有影响力的临床试验,阐述靶向药物在进展期胃癌中的地位,其中,贝伐单抗、西妥昔单抗联合氟尿嘧啶、铂类、紫杉类药物均表现出较好的疗效和安全性。ＴｏＧＡ试验确立了曲妥珠单抗在治疗进展期胃癌上的地位,但靶向治疗药物在进展期胃癌治疗中广泛应用有赖于更多的临床试验证据支持。     

2020年度妇科恶性肿瘤最新研究进展及展望

妇科肿瘤领域在过去1年取得了诸多重磅性研究成果,三大常见妇科恶性肿瘤,包括宫颈癌、子宫体癌和卵巢癌,在手术治疗、辅助治疗及靶向治疗方面均有突破性进展.靶向治疗的应用使卵巢癌患者的生存状况得到了极大程度的改善,对于特定人群的卵巢癌患者,靶向治疗带来了显著的生存获益.在手术治疗方面,宫颈癌根治性手术在传统开腹手术与腹腔镜手...     

聚酰胺-胺树状大分子在卵巢癌诊断和治疗中的应用进展

聚酰胺-胺树状大分子（polyamidoamine dendrimer, PAMAMD）因具有高度枝化、结构可控、单分散性等特点,已广泛应用于生物医学领域。靶向分子修饰后的PAMAMD可作为各种客体分子的靶向载体,显著提高客体分子的生物相容性、分散稳定性和靶向性,现已广泛应用于癌症成像诊断和靶向治疗研究。本文介绍了PAMAMD靶向系统特点,并综述了近年来该系统在卵巢癌诊断和治疗中的应用,包括在循环肿瘤细胞（circulation tumor cells, CTCs）捕获、卵巢癌成像诊断和靶向治疗中的应用,最后讨论了该系统在卵巢癌研究中所面临的挑战及应用前景。