Promising molecular targeted therapies in breast cancer

In recent years, there has been a significant improvement in the understanding of molecular events and critical pathways involved in breast cancer. This has led to the identification of novel targets and development of anticancer therapies referred to as targeted therapy. Targeted therapy has high specificity for the molecules involved in key molecular events that are responsible for cancer phenotype such as cell growth, survival, migration, invasion, metastasis, apoptosis, cell-cycle progression, and angiogenesis. Targeted agents that have been approved for breast cancer include trastuzumab and lapatinib, directed against human epidermal growth factor receptor 2 (HER2) and bevacizumab, directed against vascular endothelial growth factor (VEGF). Several other targeted agents currently under evaluation in preclinical and clinical trials include inhibitors of epidermal growth factor receptor (EGFR), dual EGFR and HER2 inhibitors, VEGF/VEGFR inhibitors, and agents that interfere with crucial signaling pathways such as PI3K/AKT/mTOR and RAS/MEK/ERK; agents against other tyrosine kinases such as Src, insulin-like growth factor (IGF)/IGF-receptor (IGFR); agents that promote apoptosis such as Poly ADP ribose polymerase inhibitors; agents that target invasion and metastasis such as matrix metalloproteinases inhibitors and others. In this review, we highlight the most promising targeted agents and their combination with mainstream chemotherapeutic drugs in clinical trials.     

Novel targeted agents in the treatment of lung cancer

Lung cancer is the leading cause of cancer-related mortality in the US. Although an improvement in outcome is possible with the continued advancement of cytotoxic-based treatment, clinical research is currently focused on utilising novel molecular targets with proven efficacy in preclinical models and a low toxicity profile. This is the result of advances in understanding of tumour biology and molecular pathways that have been implicated in cancer pathogenesis and progression. Novel agents targeting cell cycle regulation, angiogenesis and signal transduction pathways have reached clinical testing in lung cancer and are discussed in this review.     

Investigational targeted therapies for the treatment of testicular germ cell tumors

Introduction: Germ cell tumors (GCTs) are the most common malignancy among men aged between 15 to 45. Despite high cure rates of >90% over all GCTs, 3 to 5% of patients will still die of platinum-refractory disease. New systemic treatment options are needed to improve treatment success in this challenging setting.

Areas covered: To review targeted treatment options and preclinical developments in platinum-refractory GCTs, a comprehensive literature search of PubMed, Medline and scientific meeting abstracts on published clinical trials and reports on molecularly targeted approaches was conducted. Outcomes of platinum-refractory disease and of patients failing high-dose chemotherapy remain poor. Currently, no molecularly targeted treatment has shown clinically meaningful activity in unselected patient populations in clinical trials, but individual patients may achieve short-lived objective responses by treatment with sunitinib, brentuximab vedotin or imatinib. Targeted trials based on molecular selection of patients have not yet been performed.

Expert opinion: The limited activity of targeted agents in refractory GCT is disappointing. Assessment of druggable biomarkers and marker-stratified treatment may help individual patients, but is largely lacking. The low incidence and high curability of GCTs make the design of larger clinical trials difficult. The potential of novel agents, i.e. immune-checkpoint inhibitors, remains to be elucidated.     

乳腺癌靶向治疗的新策略

目前,乳腺癌的常规治疗手段如化疗、放疗等存在严重的全身副作用,为此,开展乳腺癌的靶向治疗研究具有重大意义。本文综述了乳腺癌靶向治疗的3个研究领域:抗体介导的靶向、微载体介导的靶向、乳腺癌干细胞靶向,并阐述这些治疗策略的基本研究思路,分析这些新的治疗策略面临的一些问题,从而提出解决这些问题的相关见解。     

胰腺癌分子靶向治疗现状及进展

胰腺癌是恶性程度较高的消化系统肿瘤之一,常规治疗效果有限,5年生存率只有5％左右。随着分子生物学研究的进展,EGFR抑制剂、VEGF抑制剂以及基质金属蛋白酶抑制剂等分子靶向药物的研究成为热点之一,本文着重介绍分子靶向治疗的研究现状及进展。     

Ligand-based targeted therapy for cancer tissue

Background: Limited accessibility of drugs to the tumor tissues, the requirement of high doses, intolerable cytotoxicity, the development of multiple drug resistance and non-specific targeting are obstacles to the clinical use of cancer drugs and cancer therapy. Objective: Drug delivery through carrier systems to cancerous tissue is no longer simply wrapping up cancer drugs in a new formulation for different routes of delivery, rather the focus is on targeted cancer therapy. Methods: This review summarizes the exploitation of drug-loaded nanocarrier conjugates with various targeting moieties for the delivery and targeting of anticancer drugs and describes the current status of and challenges in the field of nanocarrier-aided drug delivery and drug targeting. Conclusion: The discovery of targeting ligand to cancer cells and the development of ligand-targeted therapy will help us to improve therapeutic efficacy and reduce side effects. Unlike other forms of therapy, it will allow us to maintain quality of life for patients, while efficiently attacking the cancer tissue. It indicates that ligands have a pivotal role in cancer cell targeting.     

放疗联合靶向药物治疗食管癌的研究进展

在我国,食道癌是癌症死亡的第四大最常见的原因,严重威胁人类的健康。手术是食管癌治疗的重要方式,但对于不可手术的进展期食管癌患者,放化疗是其标准的治疗方式。然而目前的治疗方式预后仍然欠佳。因此,有必要开发更有效的新药融入该综合治疗模式中。靶向药物联合放疗在头颈部肿瘤治疗中已被证实能使患者获益。本综述集中阐述了在食管癌治疗中靶向药物的安全性及有效性,同时指出靶向药物与放射治疗相结合显示了良好的耐受性及令人满意的近期疗效,值得更深入的临床试验进一步研究。     

纳米药物在肝癌靶向治疗中的研究进展

目的了解肝癌靶向治疗的纳米药物种类及不同靶向机制,为纳米药物的进一步研发提供参考。方法对国内外相关文献进行归纳和综述。结果和结论纳米药物在肝癌靶向治疗中有着独特的优势,具有广阔的研究和开发前景。     

非小细胞肺癌靶向药物的开发研究进展

根据美国药物研究与生产商协会(PhRMA)的报告和《新药数据库》等公布的信息,对目前国际上进入III期临床试验的16种非小细胞肺癌(NSCLC)靶向新药进行分析。参照国内相关文献和美国国立癌症研究所对靶向药物的分类,将这16种新药分为EGFR靶向药物、VEGF靶向药物、多靶点抑制剂,新靶点抑制剂。经进一步分析和总结,进入III期临床试验的NSCLC靶向新药主要有以下3个特点:一是呈现多样化,多靶点抑制剂和新靶点抑制剂占87.5%;二是治疗性疫苗崭露头角,治疗性疫苗在未来几年内有可能成为抗NSCLC药物中的新成员;三是将已获得批准用于其他癌症的靶向药物用于治疗NSCLC的临床试验。说明国际制药公司充分利用现有资源开发出更多的抗NSCLC药物。     

肿瘤分子靶向治疗药物的应用进展

分子靶向治疗作为肿瘤治疗的新手段,正以其低毒、副反应和高治疗效果成为肿瘤治疗研究的热点.按作用靶点以及药物的性质,分子靶向药物可分为数类,主要包括以EGFR为靶点的药物、作用于HER2/erbB2的单克隆抗体、靶向VEGF/VEGFR的药物、以白细胞CD为靶点的单克隆抗体以及作用于多个靶点的药物.本文综述肿瘤分子靶向治...     

新的靶向治疗对于小细胞肺癌疗效的Meta分析

目的评价新的靶向治疗对于小细胞肺癌的临床疗效。方法提取发表于1990～2011年间,对比靶向治疗与无靶向治疗对于小细胞肺癌SCLC患者疗效的临床试验。评价纳入研究的质量,提取有效数据,采用RevMan 5.1软件分析生存率和无进展生存率等预后相关指标。结果纳入6个前瞻性随机对照研究,共2 026例患者,其中经靶向治疗1 031例,无靶向治疗995例。Meta分析的结果显示,新的生物制剂对于SCLC的靶向治疗并不能改善患者的1年及2年总体生存率和1年及2年无进展生存率。1年和2年总体生存率(OR)以及95%可信区间(95%CI)分别为(OR:0.89,95%CI:0.74～1.06,P=0.2)和(OR:0.97,95%CI:0.76～1.23,P=0.78),1年和2年无进展生存率OR,95%CI分别为(OR:0.95,95%CI:0.76～1.17,P=0.61)和(OR:1.04,95%CI:0.78～1.39,P=0.78),生物制剂用于SCLC患者的一线治疗和维持治疗进行亚组分析结果与总体分析一致无生存优势。结论新的生物制剂靶向治疗未能改善患者SCLC结局。     

分子诊断技术和靶向治疗在乳腺癌个体化治疗中的应用

乳腺癌是一类由不同病理实体构成和具有多样临床行为表现的异质性疾病。乳腺癌分子诊断技术和靶向治疗由于特异性较强、疗效明确、不良反应相对较小,已成为继手术、放疗和化疗等传统治疗模式之后的一种全新治疗手段。本文阐述分子靶向治疗在乳腺癌个体化治疗中的现状和应用。     

Novel targeted therapies in head and neck cancer

Introduction: Molecularly targeted therapy, with the potential for increased selectivity and fewer adverse effects, hold promise in the treatment of HNSCC.

Areas covered: Targeted agents for HNSCC expected to improve the effectiveness of current therapy including HER family, Src-family kinase, cell cycle, MET, AKT, HDAC, PARP, COX inhibitors and antiangiogenesis.

Expert opinion: Epidermal growth factor receptor inhibitors are established in HNSCC and the need now is to find biomarkers for sensitivity to better select patients. Moreover, other pathway inhibitors hold significant promise and are being tested in clinical trials. Angiogenesis inhibition is likely to yield only modest efficacy alone but may augment existing standards. Lastly, one clinical arena where targeted therapies may find secure purchase is in the adjuvant or prevention setting where minimal or preneoplastic disease can be affected by inhibition of a single or few targets.     

肿瘤干细胞靶向治疗

多种肿瘤中都存在肿瘤干细胞(cancer stem cell,CSC),这部分细胞具有自我更新能力和分化潜能,是肿瘤生长、增殖和转移的根源。此外,肿瘤干细胞具有正常干细胞的自我保护特性,如有效的DNA修复、高表达多药耐药型膜转运蛋白以及处于相对静止状态及拥有特定的微环境,使其能够逃逸现有的肿瘤治疗手段,导致肿瘤复发。针对这些保护机制,并利用肿瘤干细胞与正常干细胞的之间的差异进行靶向治疗,可能达到根治肿瘤的疗效。     

Opportunities and obstacles of targeted therapy and immunotherapy in small cell lung cancer

Abstract

Small cell lung cancer (SCLC) is an aggressive malignant tumour which accounts for approximately 13–15% of all newly diagnosed lung cancer cases. To date, platinum-based chemotherapy are still the first-line treatments for SCLC. However, chemotherapy resistance and systemic toxicity limit the long-term clinical outcome of first-line treatment in SCLC. Recent years, targeted therapy and immunotherapy have made great breakthrough in cancer therapy, and researchers aim to exploit both as a single agent or in combination with chemotherapy to improve the survival of SCLC patients, but limited effectiveness and the adverse events remain the major obstacles in the treatment of SCLC. To overcome these challenges for SCLC therapies, prevention and early diagnosis for this refractory disease is very important. At the same time, we should reveal more information about the pathogenesis of SCLC and the mechanism of drug resistance. Finally, new treatment strategies should also be taken into considerations, such as repurposing drug, optimising of targets, combination therapy strategies or prognostic biomarkers to enhance therapeutic effects and decrease the adverse events rates in SCLC patients. This article will review the molecular biology characteristics of SCLC and discuss the opportunities and obstacles of the current therapy for SCLC patients.     

Emerging targeted therapies for melanoma

Introduction: Melanoma is an aggressive cutaneous malignancy associated with poor response to traditional therapies. Recent regulatory approval for immune checkpoint inhibitors and agents targeting mutated BRAF has led to a tremendous expansion of effective treatment options for patients with advanced melanoma. Unfortunately, primary or acquired resistance develops in most patients, highlighting the need for additional therapies. Numerous genetic and other molecular features of this disease may provide effective targets for therapy development.

Areas covered: This article reviews available melanoma treatments, including immune and molecularly-targeted therapies. We then discuss agents in development, with a focus on targeted (rather than immune) therapies. In particular, we discuss agents that block mitogen-activated protein kinase (MAPK) signaling, as well as other emerging approaches such as antibody-drug conjugates, cell-cycle targeting, and novel genetically-informed clinical trials.

Expert opinion: Despite the incredible advances in melanoma therapeutics over the last several years, a clear need to develop more effective therapies remains. Molecularly-targeted therapy approaches will likely remain a cornerstone of melanoma treatment in parallel to immune therapy strategies.     

Emerging molecular targeted therapies in the treatment of head and neck cancer

Current development of molecular targeted therapies in oncology is particularly active. The aim of this study is to review recent advances in the field of molecular targeted therapies for head and neck squamous cell carcinoma (HNSCC). As EGFR signaling pathway and angiogenesis play a key role in the growth of HNSCC, EGFR with its downstream effectors and molecular factors implicated in the angiogenesis process, such as VEGF and its receptors, represent the main targets of the new therapeutic agents now in development. Today, cetuximab, an anti-EGFR monoclonal antibody, is the only targeted therapy approved for the treatment of HNSCC in patients with locally advanced tumors, in association with radiotherapy, and in patients with recurrent or metastatic diseases. Future progress is expected with the integration of cetuximab into induction chemotherapeutic regimens or in association with concurrent chemoradiotherapy for locally advanced tumors and with the development and evaluation of other molecular targeted therapies such as antiangiogenic drugs. As these innovative molecules start to be used in clinical practice, the identification of predictive markers for efficacy and toxicity becomes a crucial issue.     

Novel treatments and therapies in development for pancreatic cancer

Until recently, 5-fluorouracil was the most widely used treatment for non-resectable pancreatic cancer. This treatment, however, only resulted in a median survival time of ~ 4 months. In the last few years, gemcitabine has rapidly become the new treatment benchmark, due more to its superior clinical benefit rather than to it conferring an increased median survival (～ 5 – 6 months). Thus, the outlook for patients with pancreatic cancer is still relatively bleak. A number of new treatment options are presently being investigated. Some of these are combination therapies involving gemcitabine and other chemotherapeutic agents or radiation. Other novel treatment strategies are also already being evaluated in clinical studies. Some of the more promising treatments in development are discussed and evaluated in this article.     

食管癌的靶向治疗与免疫治疗研究进展

食管癌是一种在全球发病率和致死率都极高的恶性肿瘤,其致病因素复杂、多样,早期无明显症状,大部分患者在初诊时已是中晚期,预后差。常规手术切除结合放化疗的治疗模式已经不能满足当前疾病的治疗需求,亟需寻找新的治疗策略。分子靶向治疗和免疫治疗是近些年兴起的新型治疗方法,打破了食管癌的治疗瓶颈,已经成为食管癌治疗的重要组成部分。该研究就目前食管癌分子靶向治疗和免疫治疗的主要靶点及其相关靶向药物的研究进展进行综述,为精准医学在食管癌领域的应用提供借鉴。     

An update on first line therapies for metastatic breast cancer

Introduction: In recent years, outcomes of patients with metastatic breast cancer (MBC) have improved due to a greater understanding of the mechanisms of carcinogenesis in the development of newer molecularly targeted drugs, especially those as a front-line therapy. Remarkable improvements have been made in the treatment of hormone receptor positive (HR+) and Her2 positive MBC and currently targeted treatment strategies represent a valid first line treatment.

Areas covered: Herein, the authors provide an overview of the first-line pharmacotherapies currently available for the treatment of MBC and provide their expert perspectives on the area.

Expert opinion: Decisions on the first-line treatment of MBC should consider the clinical features of the disease, but also the biological mechanisms that regulate tumor cell growth. New and effective therapeutic agents have recently been introduced in the first-line therapy of MBC. However, to optimize the treatment of patients with metastatic disease, clinicians need biomarkers of resistance or sensitivity to targeted therapies. Efforts must also be made in developing strategies to personalize treatments of MBC patients and to identify those patients who might gain the most benefit from new treatment interventions, to save costs and limit toxicity.