HER-2-positive gastric cancer accompanied by liver metastasis: a case report of a rare complete response and literature review

The prognosis of advanced gastric cancer is poor, and the prognosis of late-stage gastric cancer with expression of human epidermal growth factor receptor 2 (HER-2) is worse. Personalized therapy is based on the specific situation of each patient to determine the best treatment plan. We diagnosed a 36-year-old patient with a HER-2-producing adenocarcinoma of the gastric cardia accompanied by liver metastasis. Sixteen cycles of chemotherapy were consecutively administered to the patient, starting with a three-drug combination, followed by a two-drug combination, and finally a single drug as a chemotherapy regimen. During these treatments, the molecular targeted drug trastuzumab was continuously administered. In the end, the patient experienced a complete response (CR). In clinical practice, advanced gastric cancer is not well controlled in certain patients, due to inadequate first-line chemotherapy and its side-effects. If a patient enjoys a strong performance status (PS), we emphasize the importance of molecular-targeted drugs combined with prolonged administration of chemotherapy.     

Research progress of antibody-drug conjugates therapy for HER2-low expressing gastric cancer

Gastric cancer (GC) is a highly fatal malignant tumor in the world. Most of the patients are in an unresectable state when they have symptoms. Systemic treatment is the primary treatment for advanced patients. Among them, the Human epidermal growth factor receptor 2 (HER2) is an important therapeutic target. With the continuous optimization of chemotherapeutic drugs and chemotherapy regimens, the prognosis of some HER2-positive GC patients has been greatly improved. However, the needs of GC patients with a low level of HER2 expression still need to be met. Several targeted drugs against human epidermal growth factor receptor 2 emerged in recent years, including Antibody-drug Conjugates (ADC), novel humanized anti-HER2 monoclonal antibodies, and Tyrosine kinase inhibitors (TKI). As an important breakthrough in treating HER2-positive GC, ADC became one of the fastest-growing anti-tumor drugs. Some drugs also showed an anti-tumor effect on GC with low expression of HER2. It may also be the key to the treatment of low expression of HER2 GC in the future. This article mainly reviews several promising ADC drugs for the treatment of HER2 low-expression GC and related trials.     

肝素结合表皮生长因子及其在恶性肿瘤中的作用

肝素结合表皮生长因子属表皮生长因子超家族成员之一,可促进多种细胞分裂和增殖,参与多个病理生理过程。近年研究发现肝素结合表皮生长因子可参与肿瘤发生发展的各个环节,在肿瘤化疗耐药中也发挥一定作用,使其成为恶性肿瘤生物学治疗的靶向因子。其与白喉毒素结合的特性为临床提供了一种新的治疗癌症的途径。继续对HB-EGF进行深入的研究,并将已获得的知识与临床治疗结合,将有望产生新的治疗恶性肿瘤的途径及新型的抗肿瘤药物。     

Recent advances and novel agents for gastrointestinal stromal tumor (GIST)

Contemporary advancements have had little impact on the treatment of gastric cancer (GC), the world??s second highest cause of cancer death. Agents targeting human epidermal growth factor receptor mediated pathways have been a common topic of contemporary cancer research, including monoclonal antibodies (mAbs) and receptor tyrosine kinase inhibitors (TKIs). Trastuzumab is the first target agent evidencing improvements in overall survival in HER2-positive (human epidermal growth factor receptor 2) gastric cancer patients. Agents targeting vascular epithelial growth factor (VEGF), mammalian target of rapamycin (mTOR), and other biological pathways are also undergoing clinical trials, with some marginally positive results. Effective targeted therapy requires patient selection based on predictive molecular biomarkers. Most phase III clinical trials are carried out without patient selection; therefore, it is hard to achieve personalized treatment and to monitor patient outcome individually. The trend for future clinical trials requires patient selection methods based on current understanding of GC biology with the application of biomarkers.     

The role of the CXCR4/CXCL12 axis and its clinical implications in gastric cancer

Gastric cancer is the second leading cause of cancer deaths worldwide. Despite the extensive body of research on gastric cancer, the prognosis of patients with advanced gastric cancer remains poor, and therapy for advanced gastric cancer relies largely on cytotoxic chemotherapy. Therefore, identifying the distinct molecular pathways underlying disease progression and treatment resistance may lead to novel therapeutic approaches, as well as improve the quality of life and survival of patients. The chemokine CXCL12 and its receptor CXCR4 are now known to play an important role in cancer development and progression. Here, we review the expression and function of CXCR4 and CXCL12, as well as their clinical relevance in gastric cancer. We also cover the current molecular mechanism, specifically the cell-signaling pathway, by which gastric cancer progresses through the CXCR4/CXCL12 axis, and discuss the potential of that axis as a therapeutic target in the treatment of gastric cancer.     

以EGFR为靶点的肿瘤分子靶向药物研究进展

随着分子生物学研究的进展,分子靶向治疗已成为除手术、放疗、化疗之外的第4种治疗方法,越来越多的用于临床治疗恶性肿瘤。分子靶向药物进入体内能够特异地选择致癌位点,杀伤肿瘤细胞,而不会波及周围正常的组织细胞,因此分子靶向治疗又被称为"生物导弹"。与传统化疗药物相比,分子靶向药物具有特异性强、疗效明显、副作用少等优点。按照分子靶向药物的性质主要归为两大类:一类是单克隆抗体,如西妥昔单抗等;另一类是单靶点或多靶点的小分子抑制剂,如吉非替尼等。表皮生长因子受体(EGFR)对肿瘤的生长、发展以及肿瘤干细胞的维持都有着非常重要的作用,并且在多种实体瘤中存在过表达或异常表达,因此在肿瘤治疗中,EGFR成为一个非常重要的用药靶点。现主要对目前国内已上市的针对EGFR的分子靶向药物最新的临床研究进展作一简要综述。     

非小细胞肺癌分子靶向药物治疗的研究进展

非小细胞肺癌(NSCLC)为最常见的肺癌病理类型,约占肺癌总数的 85%。大多数肺癌患者在确诊时已属晚期,失去手术机会, 保守治疗成为其重要治疗手段,但晚期肺癌患者的预后仍不理想。近年来,分子靶向治疗在肿瘤治疗领域取得重要进展,亦有研究显示 其在 NSCLC 的临床实践中发挥显著疗效。除表皮生长因子受体(EGFR)和间变淋巴瘤激酶(ALK)等主要基因突变之外,血管内皮生 长因子(VEGF)、ROS1、c-MET、RET、K-RAS、BRAF 也是目前 NSCLC 分子靶向治疗的相关靶点。综述 NSCLC 分子靶向药物治疗 的研究进展,旨在为该疾病的治疗提供参考。     

胃癌的过继性免疫治疗研究进展

胃癌是目前世界上发病率及致死率较高的恶性肿瘤之一,在东亚地区尤其显著。针对胃癌的治疗手段仍是传统的手术联合化疗、放疗为主,尽管靶向药物治疗提供了新的选择,但其对晚期胃癌的疗效仍然有限。胃癌的免疫治疗作为独特的治疗手段,在近十多年发展较为活跃,特别是过继性免疫治疗手段不断有创新。过继性免疫治疗主要依赖回输具有抗肿瘤活性的细胞,目前回输的细胞由具有非特异性抗肿瘤作用向具有特异性抗肿瘤作用演变,特别是嵌合性抗原T细胞治疗的出现,为进展期胃癌患者提供了有一种潜在的选择。本文对胃癌过继性免疫治疗中采用的不同免疫活性细胞的作用机制、临床应用等进行总结,并针对其不足提出利用基因工程技术增强治疗靶向性、降低免疫逃逸的研究方向。     

Phase 2 study of canfosfamide in combination with pegylated liposomal doxorubicin in platinum and paclitaxel refractory or resistant epithelial ovarian cancer

We have reviewed the pivotal presentations related to gastrointestinal malignancies from 2009 annual meeting of the American Society of Clinical Oncology with the theme of "personalizing cancer care". We have discussed the scientific findings and the impact on practice guidelines and ongoing clinical trials. Adding trastuzumab to chemotherapy improved the survival of patients with advanced gastric cancer overexpressing human epidermal growth factor receptor 2. Gemcitabine plus cisplatin has become a new standard for first-line treatment of advanced biliary cancer. Octreotide LAR significantly lengthened median time to tumor progression compared with placebo in patients with metastatic neuroendocrine tumors of the midgut. Addition of oxaliplatin to fluoropyrimidines for preoperative chemoradiotherapy in patients with stage II or III rectal cancer did not improve local tumor response but increased toxicities. Bevacizumab did not provide additional benefit to chemotherapy in adjuvant chemotherapy for stage II or III colon cancer. In patients with resected stage II colon cancer, recurrence score estimated by multigene RT-PCR assay has been shown to provide additional risk stratification. In stage IV colorectal cancer, data have supported the routine use of prophylactic skin treatment in patients receiving antibody against epidermal growth factor receptor, and the use of upfront chemotherapy as initial management in patients with synchronous metastasis without obstruction or bleeding from the primary site.     

Structure-Activity Relationship of Indole-Tethered Pyrimidine Derivatives that Concurrently Inhibit Epidermal Growth Factor Receptor and Other Angiokinases

Antiangiogenic agents have been widely investigated in combination with standard chemotherapy or targeted cancer agents for better management of advanced cancers. Therapeutic agents that concurrently inhibit epidermal growth factor receptor and other angiokinases could be useful alternatives to combination therapies for epidermal growth factor receptor-dependent cancers. Here, we report the synthesis of an indole derivative of pazopanib using a bioisosteric replacement strategy, which was designated MKP101. MKP101 inhibited not only the epidermal growth factor receptor with an IC₅₀ value of 43 nM but also inhibited angiokinases as potently as pazopanib. In addition, MKP101 effectively inhibited vascular endothelial growth factor-induced endothelial proliferation, tube formation, migration of human umbilical vein endothelial cells and proliferation of HCC827, an epidermal growth factor receptor-addicted cancer cell line. A docking model of MKP101 and the kinase domain of the epidermal growth factor receptor was generated to predict its binding mode, and validated by synthesizing and evaluating MKP101 derivatives. Additionally, a study of structure-activity relationships of indolylamino or indolyloxy pyrimidine analogues derived from MKP101 demonstrated that selectivity for epidermal growth factor receptor and other angiokinases, especially vascular endothelial growth factor receptor 2 depends on the position of substituents on pyrimidine and the type of link between pyrimidine and the indole moiety. We believe that this study could provide a basis for developing angiokinase inhibitors having high affinity for the epidermal growth factor receptor, from the pyrimidine scaffold.     

应用siRNA干扰胃癌的研究进展

胃癌是消化系统最常见的恶性肿瘤,而我国是胃癌高发区,其发病率和死亡率均高于世界平均水平。在我国大多数患者明确诊断时已进入进展期,所以大多数患者再行手术切除后还需放化疗治疗。近来随着对胃癌的研究深入,可通过对胃癌肿瘤标本行分子检测给予患者药物靶向治疗,实现个体化治疗。RNA干涉(RNAi)技术被广泛用于基因功能的研究,并且在哺乳动物研究中得到飞速发展.si RNA是在RNAi中起中心作用,其可抑制特定m RNA,以调节不同蛋白在肿瘤发生时的异常表达。对si RNA的研究将为胃癌的基因治疗供更广阔的空间。     

Targeting erbB receptors

Our work is concerned with the origins and therapy of human cancers. Members of the epidermal growth factor receptor (EGFR) family of tyrosine kinases, also known as erbB or HER receptors, are over expressed and/or activated in many types of human tumors and represent important therapeutic targets in cancer therapy. Studies from our laboratory identified targeted therapy as a way to treat cancer. Rational therapeutics targeting and disabling erbB receptors have been developed to reverse the malignant properties of tumors. Reversal of the malignant phenotype, best seen with disabling the HER2 receptors using monoclonal antibodies is a distinct process from that seen with blocking of ligand binding to cognate receptors as has been done for EGFr receptors. Here we review the mechanisms of action deduced from a number of approaches developed in our laboratory and elsewhere, including monoclonal antibodies, peptide mimetics, recombinant proteins and small molecules. The biochemical and biological principles which have been uncovered during these studies of disabling HER2 homomeric or HER2-EGFr heteromeric receptors will help the development of novel and more efficient therapeutics targeting erbB family receptors.     

Cancer cell-selective in vivo near infrared photoimmunotherapy targeting specific membrane molecules

Three major modes of cancer therapy (surgery, radiation and chemotherapy) are the mainstay of modern oncologic therapy. To minimize the side effects of these therapies, molecular-targeted cancer therapies, including armed antibody therapy, have been developed with limited success. In this study, we have developed a new type of molecular-targeted cancer therapy, photoimmunotherapy (PIT), that uses a target-specific photosensitizer based on a near-infrared (NIR) phthalocyanine dye, IR700, conjugated to monoclonal antibodies (mAbs) targeting epidermal growth factor receptors. Cell death was induced immediately after irradiating mAb-IR700-bound target cells with NIR light. We observed in vivo tumor shrinkage after irradiation with NIR light in target cells expressing the epidermal growth factor receptor. The mAb-IR700 conjugates were most effective when bound to the cell membrane and produced no phototoxicity when not bound, suggesting a different mechanism for PIT as compared to conventional photodynamic therapies. Target-selective PIT enables treatment of cancer based on mAb binding to the cell membrane.     

Coding and non-coding nucleotides': The future of stroke gene therapeutics

Stroke is the foremost cause of death ranked after heart disease and cancer. It is the fatal life-threatening event that requires immediate medical admissions to overcome following morbidity and mortality. The therapeutic advances in stroke therapy have been manipulated with diverse paths for last 5 years. Recent research and clinical trials have investigated a variety of anti-stroke agents including anti-coagulants, cerebro-protective agents, antiplatelet therapy, stem-cell therapy, and specified gene therapy. In recent advanced studies, genetic therapies including noncoding RNAs (ncRNAs), long non-coding RNAs (LncRNAs), small interfering RNAs (siRNAs), microRNAs (miRNAs), Piwi interacting RNAs (PiWi RNAs) have shown better potential as targeted future therapeutics with a better outcome than conventional stroke therapeutics. The potential of targeted gene therapy is much more advanced in not only the induction of neuroprotection but also safer non-toxic targeted therapeutics. In the current state of the art review, we have focused on the recent advancements made towards the stroke with RNA modifications and targeted gene therapeutics.     

miR-301a-3p induced by endoplasmic reticulum stress mediates the occurrence and transmission of trastuzumab resistance in HER2-positive gastric cancer

Trastuzumab resistance negatively influences the clinical efficacy of the therapy for human epidermal growth factor receptor 2 (HER2) positive gastric cancer (GC), and the underlying mechanisms remain elusive. Exploring the mechanisms and finding effective approaches to address trastuzumab resistance are of great necessity. Here, we confirmed that endoplasmic reticulum (ER) stress-induced trastuzumab resistance by up-regulating miR-301a-3p in HER2-positive GC cells. Moreover, we elucidated that miR-301a-3p mediated trastuzumab resistance by down-regulating the expression of leucine-rich repeats and immunoglobulin-like domains containing protein 1 (LRIG1) and subsequently activating the expression of insulin-like growth factor 1 receptor (IGF-1R) and fibroblast growth factor receptor 1 (FGFR1) under ER stress. We also found that intercellular transfer of miR-301a-3p by exosomes disseminated trastuzumab resistance. The present study demonstrated that exosomal miR-301a-3p could serve as a non-invasive biomarker for trastuzumab resistance, which was maybe a novel potential therapeutic target to overcome trastuzumab resistance and improve the curative effect of trastuzumab in HER2-positive GC patients.Subject terms: Cancer therapeutic resistance, Gastric cancer     

Erlotinib in the treatment of non-small cell lung cancer

Because erlotinib, an epidermal growth factor receptor tyrosine kinase (EGFRTK) inhibitor, has been shown to be effective and well-tolerated as a second/third-line treatment in the therapy of advanced non-small cell lung cancer (NSCLC), this agent has been recently approved for human NSCLC therapy in the European Union. Although additive and synergistic effects of erlotinib and conventional chemotherapy were demonstrated in the combined regime preclinically, this has yet to be approved in the clinic. Since erlotinib and cytotoxic drugs have different biological targets, they have distinct side effects as well: erlotinib has no toxic effect on the bone marrow, but can cause diarrhea and rash, the latter being thought to be an indicator of the therapeutic efficacy. Several ongoing clinical trials are investigating the potential role of erlotinib in different settings in human NSCLC. This review intends to integrate our current knowledge on the erlotinib treatment in NSCLC.     

Recent advances in the treatment of gastric cancer

Gastric cancer is the 9th most common malignancy in Hungary, being the 4th most frequent cause of death among all cancers. The traditional treatment approaches did not turn out to be effective against advanced gastric cancer. On the other hand, due to better understanding of the underlying molecular biology of tumors, targeted therapeutics emerge resulting in longer survival times. Dank M. Recent advances in the treatment of gastric cancer.     

Recent advances of novel targeted therapy in non-small cell lung cancer

Lung cancer is the leading cause of cancer deaths world-wide. Recent advances in cancer biology have led to the identification of new targets in neoplastic cells and the development of novel targeted therapies. At this time, two targeted agents are approved by the FDA in advanced non-small cell lung cancer (NSCLC): the epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) erlotinib, and the anitangiogenic bevacizumab. A third agent, cetuximab, which was recently shown to enhance survival when used with cisplatin and vinorelbine as first line therapy for advanced NSCLC, will likely be approved by regulatory agencies. With more than 500 molecularly targeted agents under development, the prospects of identifying novel therapies that benefit individual patients with lung cancer are bright.