非小细胞肺癌的分子靶向治疗

与传统细胞毒性化疗相比,分子靶向治疗能更特异性作用于肿瘤而毒性反应较轻。新的靶向治疗药物得到发展,并相继在晚期非小细胞肺癌一线、二线治疗中进行临床试验,其中有的药物显示了较好的疗效。本文对近年来关于非小细胞肺癌靶向治疗的临床试验进行回顾。     

分子靶向治疗在Ⅲb/Ⅳ期非小细胞肺癌一线治疗中的应用

Ⅲb/Ⅳ期非小细胞肺癌一线化疗的疗效已进入瓶颈期.分子靶向药物的出现,给晚期非小细胞肺癌的一线治疗带来了划时代的变革,极大地改善了晚期非小细胞肺癌患者的生活质量、提高了生存期.全文就分子靶向治疗在晚期非小细胞肺癌一线治疗中的应用作一综述.     

非小细胞肺癌脑转移靶向治疗研究进展

肺癌最常见的远处转移部位之一是脑部,肺癌脑转移的发生率为20%-65%,是脑转移性肿瘤中最常见的类型,同时也是肺癌死亡率高居不下的原因之一。分子靶向治疗已成为肺癌治疗的重要手段,分子靶向药物也成为继全脑放疗、立体定向放疗和化疗之后肺癌脑转移新的治疗方法。目前,对脑转移的非小细胞肺癌患者应用靶向药物治疗的研究也越来越多,其安全性和有效性是研究的重点。本文就靶向药物治疗非小细胞肺癌脑转移的研究进展做一综述。     

非小细胞肺癌EGFR-TKI基因检测

在世界范围内,肺癌是导致恶性肿瘤患者死亡的主要原因[1]。肺癌从病理学上大体分为非小细胞肺癌(NSCLC)和小细胞肺癌(SCLC),其中NSCLC约占80%,且传统的化疗、放疗已进入平台期。随着生物治疗在肿瘤治疗研究的全方位发展以及分子靶向治疗药物的多层次研究,一种新的分子靶向药物EGFR酪氨酸激酶抑制剂(TKI)成功应用     

免疫治疗联合化疗、放疗及靶向药物治疗小细胞肺癌脑转移的研究进展

小细胞肺癌脑转移是一个治疗难题,传统治疗方式存在局限性。免疫治疗与化疗、放疗及靶向药物联合治疗为小细胞肺癌脑转移患者提供了一种新的选择。化疗联合免疫治疗逐渐成为广泛期小细胞肺癌的一线治疗,其对脑转移亚组的疗效也得到一定证实。脑部放射治疗联合免疫治疗是一种思路,尽管指南未明确提及联合方式,但从分子机制及小样本研究来看,其组合方式倾向于推荐同步治疗。抗血管生成药物联合免疫治疗疗效优于单药,不良反应也在可接受范围内。全文主要阐述免疫疗法治疗小细胞肺癌脑转移的最新进展,并进一步探讨其与化疗、放疗以及靶向药物联合治疗所带来的疗效及相关不良反应。     

小细胞肺癌靶向治疗的研究进展

摘 要：小细胞肺癌（small cell lung cancer,SCLC）约占全部肺癌的15%~20%,其生物学行为表现为恶性程度高、侵袭性强、预后差。尽管初始治疗时对放、化疗敏感,但小细胞肺癌患者容易早期出现复发转移,因疾病进展后缺乏有效治疗手段,最终导致患者死亡。近十年,靶向治疗的发展给非小细胞肺癌的治疗策略带来了巨大改变。SCLC同样具有大量体细胞突变,针对不同靶点的分子靶向药物在SCLC患者治疗中亦进行了很多探索。虽然目前没有有效的靶向药物被批准用于治疗SCLC,一些新的靶向药物在临床研究中的疗效给SCLC的治疗带来了曙光。全文将对SCLC靶向治疗的研究现状及进展进行综述。     

非小细胞肺癌的分子靶向治疗进展

目前在全球范围内肺癌已成为发病率和死亡率增长最快、严重危害人类健康和生命的恶性肿瘤之一.在我国肺癌病死率已居肿瘤死亡率首位,其中非小细胞肺癌(NSCLC)约占肺癌的80%以上,且多数患者确诊时已属晚期,因此内科治疗仍是肺癌的主要治疗方法.但近十年来以化疗为主的治疗手段并未使非小细胞肺癌的疗效获得突破性进展.20世纪90年代以来,关于肺癌的分子靶向治疗研究不断深入,其中以表皮生长因子受体和肿瘤血管生成作为靶点的药物为主,部分药物已经在晚期NSCLC治疗中显示出较好的临床疗效.21世纪分子靶向治疗已取得了飞跃的进展,许多新的靶向性治疗研究为NSCLC治疗提供新的治疗途径.本研究将从以表皮生长因子受体为靶点药物,抗肿瘤血管生成药物以及多靶点抗肿瘤药物3个方面就目前非小细胞肺癌靶向治疗的研究进展作一介绍.     

小细胞肺癌的治疗现状与进展

小细胞肺癌占肺癌总数的15%～20%,具有增殖快、早期转移等特点。尽管其对放、化疗比较敏感,但中位生存期仍然较短。EP/EC方案依旧是局限期小细胞肺癌的标准一线化疗方案。Irinotecan开始成为广泛期小细胞肺癌的一线用药。早期同步放化疗可提高局限期小细胞肺癌的生存率。根治性手术可延长部分早期小细胞肺癌患者的生存时间。单用imatinib疗效较差,联合其他药物可能会提高疗效。Gefitinib已被证实对小细胞肺癌的治疗无效。Temsirolimus有望成为治疗SCLC新的分子靶向药物。     

化疗序贯EGFR-TKIs治疗晚期非小细胞肺癌的机制及疗效

随着肿瘤分子生物学研究的发展,表皮生长因子受体酪氨酸激酶抑制剂(EGFR-TKIs)在晚期非小细胞肺癌治疗中占有重要地位,特别针对于EGFR突变型患者.但基于分子靶向药物并未明显改善患者的总生存时间及出现获得性耐药问题,如何将传统化疗药物与靶向药物有机结合延长晚期患者的总生存时间受到广泛关注.化疗序贯EGFR-TKIs模式被证实为其中一项颇有前景的治疗策略.本文将结合相关研究对化疗序贯EGFR-TKIs治疗晚期非小细胞肺癌(NSCLC)的机制及疗效进行综述.     

怎样选择肺癌的治疗方案

肺癌可分为小细胞肺癌和非小细胞肺癌两大类,后者占全部肺癌的85％. 两大类肺癌的治疗方法完全不一样,所以确诊为肺癌时,必须有病理结果.第一是根据病理确定诊断;第二是根据病理确定肺癌属于哪一大类,明确决定最佳治疗方案;第三是如果对病理标本进行基因谱测定和对抗癌化疗药物敏感性测定,在选择化疗药物时,治疗就会有针对性,在选择分子靶向药物治疗时就有了依据,不会盲目用药,既浪费了金钱,又耽误了病情.     

Clinical impact of novel treatment strategies

Following two decades of research on the biology of cancer and in particular of lung cancer, we have now a large number of molecular targets that can be utilized to create specific medicines against these cancers. Non-small cell lung cancer represents numerically the most important solid tumor in Western world, and is poorly affected by current therapies, where surgery represents almost the only curative therapy for about 25% of patients who are resectable at diagnosis. An abundant number of targeted therapies are being investigated in NSCLC. Among them are the metalloproteinase inhibitors, several tyrosine kinase inhibitors and several attempts of gene replacement have also been made. Promising results have so far been obtained with some of these approaches, and the outcome of large randomized studies is awaited. Small cell lung cancer (SCLC) represents about 20% of lung carcinomas, and several of the novel approaches that are being attempted for NSCLC, are also being investigated for SCLC. All these novel therapies open a new era of anticancer treatment that will likely complement the currently available therapies in the near future.     

Molecular subtyping of small-cell lung cancer based on mutational signatures with different genomic features and therapeutic strategies

Small-cell lung cancer (SCLC) is an exceptionally lethal malignancy characterized by extremely high alteration rates and tumor heterogeneity, which limits therapeutic options. In contrast to non-small-cell lung cancer that develops rapidly with precision oncology, SCLC still remains outside the realm of precision medicine. No recurrent and actionable mutations have been detected. Additionally, a paucity of substantive tumor specimens has made it even more difficult to classify SCLC subtypes based on genetic background. We therefore carried out whole-exome sequencing (WES) on the largest available Chinese SCLC cohort. For the first time, we partitioned SCLC patients into three clusters with different genomic alteration profiles and clinical features based on their mutational signatures. We showed that these clusters presented differences in intratumor heterogeneity and genome instability. Moreover, a wide existence of mutually exclusive gene alterations, typically within similar biological functions, was detected and suggested a high SCLC intertumoral heterogeneity. Particularly, Cluster 1 presented the greatest potential to benefit from immunotherapy, and Cluster 3 constituted recalcitrant SCLC, warranting biomarker-directed drug development and targeted therapies in clinical trials. Our study would provide an in-depth insight into the genome characteristics of the Chinese SCLC cohort, defining distinct molecular subtypes as well as subtype-specific therapies and biomarkers. We propose tailoring differentiated therapies for distinct molecular subgroups, centering on a personalized precision chemotherapy strategy combined with immunization or targeted therapy for patients with SCLC.     

小细胞肺癌药物治疗进展

小细胞肺癌（small cell lung cancer,SCLC）约占肺癌患者的13% 。与非小细胞肺癌相比具有早期转移倾向及对一线细胞毒性化疗药物敏感的特点。目前的治疗方式包括手术、胸部及脑部放疗和化疗。以铂类联合依托泊苷为标准一线化疗,治疗后复发率较高。拓扑替康单药为标准二线化疗,新型的靶向和免疫治疗等疗效均欠佳。因此小细胞肺癌的治疗亟待有新的突破。      

小细胞肺癌二线治疗进展

小细胞肺癌(SCLC)是一种恶性程度较高的肿瘤,一线放化疗非常敏感,但容易复发转移,预后差.SCLC二线治疗进展缓慢,拓扑替康是目前唯一被美国食品和药物管理局批准的二线标准治疗药物.大量关于分子靶向治疗和免疫治疗的研究正在进行中,但大多疗效欠佳.2016年美国临床肿瘤学会年会上公布的靶向Delta样蛋白3的抗体药物耦联物rovalpituzumab tesirine(Rova-T)显示了良好的抗肿瘤活性,似乎为分子靶向治疗带来了新的曙光.     

靶向抗肿瘤单克隆抗体药物应用的现状和展望

随着对抑制肿瘤信号通路、抑制肿瘤生长相关血管生成通路以及活化免疫系统发挥抗肿瘤作用等靶向抗肿瘤方法研究的不断进展,抗肿瘤抗体药物已经成为肿瘤领域不可或缺的治疗手段.临床批准的靶向抗肿瘤抗体药物主要包括分子靶向单克隆抗体(单抗)药物、抗体偶联药物、双特异性抗体药物以及靶向免疫检验点药物.近年来,肿瘤免疫治疗越发火热,上述具有免疫调节作用的抗体药物,或能增加肿瘤抗原性,或能促进肿瘤T细胞浸润,已经取得了巨大的临床收益;单抗药物的联用是未来的一大发展重点,无论是与肿瘤免疫疗法联用、与分子靶向抗体药物联用、与放化疗和小分子抑制剂药物甚至手术的联用,都将进一步提高抗体类药物在抗肿瘤治疗中的实用价值.     

Genetic changes in small cell lung carcinoma

Small cell lung carcinoma (SCLC) accounts for approximately 15% of all lung cancer cases. Despite a frequently good response to first-line treatment with chemotherapy and/or radiotherapy, early relapse occurs in the majority of patients and 5-year survival is only about 5%. Therefore, there is a need to develop novel treatments to improve the outcome of patients with SCLC. To fulfil this need, it is critical to gain further understanding on the molecular basis of SCLC and specifically to identify novel therapeutic targets. Clinical trials with molecularly targeted agents have been performed with little success in the past, but recently many promising oncogenic pathways have been discovered and novel targeted therapies are under evaluation. In this review, we summarise the most relevant genetic and signalling pathway alterations reported to date in SCLC and discuss the potential therapeutic implications of such events.     

Myc在小细胞肺癌中的研究进展

小细胞肺癌（small cell lung cancer，SCLC）是一种侵袭性恶性肿瘤，占所有肺癌诊断的14％。尽管经过了数十年的积极研究，SCLC的治疗方案仍然有限。迄今为止，SCLC还没有批准的靶向药物，因此需要进一步研究SCLC的靶向治疗。作为SCLC中常见的一种遗传畸变，Myc家族成员显得尤为突出。过去几年的研究表明，直接靶向Myc显得寸步难行，故人们广泛研究了间接抑制Myc活性的方法。在这篇综述中，我们描述了Myc的概念和它在SCLC中的作用，回顾了SCLC现有的治疗方法，总结了Myc抑制剂在SCLC中的最新研究进展。     

Small cell lung cancer: Where do we go from here?

Small cell lung cancer (SCLC) is an aggressive disease that accounts for approximately 14% of all lung cancers. In the United States, approximately 31,000 patients are diagnosed annually with SCLC. Despite numerous clinical trials, including at least 40 phase 3 trials since the 1970s, systemic treatment for patients with SCLC has not changed significantly in the past several decades. Consequently, the 5‐year survival rate remains low at <7% overall, and most patients survive for only 1 year or less after diagnosis. Unlike nonsmall cell lung cancer (NSCLC), in which major advances have been made using targeted therapies, there are still no approved targeted drugs for SCLC. Significant barriers to progress in SCLC include 1) a lack of early detection modalities, 2) limited tumor tissue for translational research (eg, molecular profiling of DNA, RNA, and/or protein alterations) because of small diagnostic biopsies and the rare use of surgical resection in standard treatment, and 3) rapid disease progression with poor understanding of the mechanisms contributing to therapeutic resistance. In this report, the authors review the current state of SCLC treatment, recent advances in current understanding of the underlying disease biology, and opportunities to advance translational research and therapeutic approaches for patients with SCLC. Cancer 2015;121:664–672. © 2014 American Cancer Society.     

Novel strategies for the treatment of small-cell lung carcinoma

Small-cell lung cancer (SCLC) is a disease with a poor prognosis and limited treatment options. Over the past 30 years, basic and clinical research have translated to little innovation in the treatment of this disease. The Study of Picoplatin Efficacy After Relapse (SPEAR) evaluated best supportive care with or without picoplatin for second-line SCLC treatment and failed to meet its primary end point of overall survival. As the largest second-line, randomized study in patients with SCLC, SPEAR provides an opportunity to critically examine the drug development model in this disease. In this Review, we discuss the current standard approach for the management of SCLC that progresses after first-line therapy, analyze the preliminary data that supported the evaluation of picoplatin in this setting, and critically evaluate the SPEAR trial design and results. Lastly, we present advances in the understanding of the molecular biology of SCLC that could potentially inform future clinical trials and hopefully lead to the successful development of molecular targeted agents for the treatment of this disease.     

Development of molecularly targeted agents and immunotherapies in small cell lung cancer

Small cell lung cancer (SCLC) is a smoking-induced malignancy with multiple toxin-associated mutations, which accounts for 15% of all lung cancers. It remains a clinical challenge with a rapid doubling time, early dissemination and poor prognosis. Despite multiple clinical trials in SCLC, platinum-based chemotherapy remains the mainstay of treatment in the first line advanced disease setting; good initial responses are nevertheless inevitably followed by disease relapse and survival ultimately remains poor. There are currently no molecularly targeted agents licenced for use in SCLC. Advances in sequencing the cancer genome and other high-throughput profiling technologies have identified aberrant pathways and mechanisms implicated in SCLC development and progression. Novel anti-tumour therapeutics that impact these putative targets are now being developed and investigated in SCLC. In this review, we discuss novel anti-tumour agents assessed in SCLC with reference to the complex molecular mechanisms implicated in SCLC development and progression. We focus on novel DNA damage response inhibitors, immune checkpoint modulators and antibody-drug conjugates that have shown promise in SCLC, and which may potentially transform treatment strategies in this disease. Finally, we envision the future management of SCLC and propose a biomarker-driven translational treatment paradigm for SCLC that incorporates next generation sequencing studies with patient tumours, circulating plasma DNA and functional imaging. Such modern strategies have the potential to transform the management and improve patient outcomes in SCLC.