Personalizing medicine for metastatic colorectal cancer:Current developments

Metastatic colorectal cancer(mCRC)is still one of the tumor types with the highest incidence and mortality.In 2012,colorectal cancer was the second most prevalence cancer among males(9%)and the third among females(8%).In this disease,early diagnosis is important to improve treatment outcomes.However,at the time of diagnosis,about one quarter of patients already have metastases,and overall survival of these patients at 5-years survival is very low.Because of these poor statistics,the development of new drugs against specific targets,including the pathway of angiogenesis,has witnessed a remarkable increase.So,targets therapies through epidermal growth factor and its receptor and also KRAS pathways modulation acquired a main role whether in association with standard chemotherapy and radiotherapy.With the current knowledge in the field of molecular biology,including genetic mutations and polymorphisms,we know better why patients respond so differently to the same treatments.So,in the future we can develop increasingly personalized treatments to the patient and not the disease.This review aims to summarize some molecular pathways and their relation to tumor growth,as well as novel targeted developing drugs and recently approved for mCRC.     

Liver cancer: Targeted future options

Hepatocellular carcinoma(HCC)has a poor prognosis an d systemic chemotherapies have disappointing results.The increasing knowledge of the molecular biolog y of HCC has resulted in novel targets,with the vascular endothelial growth factor and epidermal growth factor receptor(EGFR)-related pathways being of special interest.New blood vessel formation(angiogenesis)is essential for the growth of solid tumors.Anti-angiogenic strategies have become an important therapeutic modality for solid tumors.Several agents targeting angiogenesis-related pathways have entered clinical trials or have been already approved for the treatment of solid tumors.These include monoclonal antibodies,receptor tyrosine kinase inhibitors and immunomodulatory drugs.HCC is a highly vascular tumor,and angiogenesis is be-lieved to play an important role in its development and progression.This review summarizes recent advances in the basic understanding of the role of angiogenesis in HCC as well as clinical trials with novel therapeutic approaches targeting angiogenesis and EGFR-related pathways.     

EGFR靶向药物在结直肠癌中的研究进展

结直肠癌是常见的消化系恶性肿瘤,传统的化疗和放疗效果均不甚理想.表皮生长因子受体(EGFR)q%号转导通路在结直肠癌细胞的增殖、血管生成、侵袭、转移等方面有重要作用.因此,针对EGFR的靶向药物已陆续开发,并应用于结直肠癌治疗的临床实践.本文就EGFR靶向药物在结直肠癌中的研究现状及其相关问题进行综述.     

Resistance to targeted therapy in metastatic colorectal cancer: Current status and new developments

Colorectal cancer (CRC) is one of the most lethal and common malignancies in the world. Chemotherapy has been the conventional treatment for metastatic CRC (mCRC) patients. However, the effects of chemotherapy have been unsatisfactory. With the advent of targeted therapy, the survival of patients with CRC have been prolonged. Over the past 20 years, targeted therapy for CRC has achieved substantial progress. However, targeted therapy has the same challenge of drug resistance as chemotherapy. Consequently, exploring the resistance mechanism and finding strategies to address the resistance to targeted therapy, along with searching for novel effective regimens, is a constant challenge in the mCRC treatment, and it is also a hot research topic. In this review, we focus on the current status on resistance to existing targeted therapies in mCRC and discuss future developments.     

How to select the optimal treatment for first line metastatic colorectal cancer

Choice of first line treatment for patients with metastatic colorectal cancer(mCRC)is based on tumour and patient related factors and molecular information for determination of individual treatment aim and thus treatment intensity.Recent advances(e.g.,extended RAS testing)enable tailored patient assignment to the most beneficial treatment approach.Besides fluoropyrimidines,irinotecan and oxaliplatin,a broad variety of molecular targeting agents are currently available,e.g.,anti-angiogenic agents(bevacizumab)and epidermal growth factor receptor(EGFR)antibodies(cetuximab,panitumumab)for first line treatment of mCRC.Although some combinations should be avoided(e.g.,oral or bolus fluoropyrimidines,oxaliplatin and EGFR antibodies),treatment options range from single agent to highly effective four-drug regimen.Preliminary data comparing EGFR antibodies and bevacizumab,both with chemotherapy,seem to favour EGFR antibodies in RAS wildtype disease.However,choosing the most appropriate treatment approach for mCRC patients remains a complex issue,with numerous open questions.     

Irinotecan therapy and molecular targets in colorectal cancer： A systemic review

Irinotecan is the second line chemotherapy for advanced stage colorectal cancer （CRC） after failure of first line chemotherapy with oxaliplatin and 5-fluorouracil. The aim of this review is to analyse the data on irinotecan as second line chemotherapy for advanced CRC and the potential roles of the molecular markers, p53 and vascular endothelial growth factor （VEGF） in the management of advanced CRC. Thus, the English literature from 1980 to 2008 concerning irinotecan, p53, VEGF and CRC was reviewed. On review, Phase Ⅱ and Ⅲ clinical trials showed that irinotecan improves pain-free survival, quality of life, 1-year survival, progression-free survival and overall survival in advanced CRC. p53 and VEGF were expressed in CRC and had a predictive power of aggressive clinical behaviour in CRC. Irinotecan sensitizes p53 wild type, mutant and null cells to Fas- mediated cell apoptosis in CRC cells. Wild type p53 cells were more sensitive to irinotecan than mutated p53. Irinotecan has an anti-VEGF effect inhibiting endothelial cell proliferation, increasing apoptosis and reducing microvascular density which is only limited by irinotecan toxicity levels. To conclude, irinotecan improves the patient＇s quality of life and the survival rates of patients with advanced CRC. p53 and VEGF status of the patients＇ tumour is likely to affect the responsiveness of CRC to irinotecan. It is recommended that studies of the expression of these molecular markers in relation to chemoresponsiveness of irinotecan should be carried out for better management of patients with advanced CRC.     

Current and emerging medical treatments for non-small cell lung cancer: a primer for pulmonologists

Pulmonary physicians commonly develop relationships with lung cancer patients through the evaluation and staging of the disease prior to the discussion of treatment options with oncologists. Given the relationship that develops, a pulmonologist is often asked about aspects of the treatment plan that may be slightly outside of their comfort zone. The aim of this overview of medical treatment of non-small cell lung cancer is to provide the pulmonologist with an overview of the evidence guiding current practice so that they can be more comfortable answering their patients' questions while awaiting the expert opinion of the oncologist. We discuss standard chemotherapeutic agents, their common side effects, and their use in the adjuvant and neoadjuvant setting, as definitive therapy for locally advanced disease, as palliative therapy for advanced disease, and as maintenance therapy. We also discuss the mechanisms of action and side effects of targeted therapies (including inhibitors of vascular endothelial growth factor [VEGF], epidermal growth factor receptor [EGFR] signaling and the anaplastic lymphoma kinase [ALK] protein), their currently accepted uses, and upcoming phase III trials, the results of which may influence standard practice.     

VEGF-D expression correlates with colorectal cancer aggressiveness and is downregulated by cetuximab

AIM： To gain mechanistic insights into the role played by epidermal growth factor receptor （EGFR） in the regulation of vascular endothelial growth factors （VEGFs） in colorectal cancer （CRC）. METHODS： The impact of high-level expression of the growth factor receptors EGFR and VEGF receptor （VEGFR）3 and the VEGFR3 ligands VEGF-C and VEGF-D on disease progression and prognosis in human CRC was investigated in 108 patients using immu- nohistochemistry. Furthermore, the expression of the lymphangiogenic factors in response to the modulation of EGFR signalling by the EGFR-targeted monoclonal antibody cetuximab was investigated at the mRNA and protein level in human SW480 and SW620 CRC cell lines and a mouse xenograft model. RESULTS： Human CRC specimens and cell lines displayed EGFR, VEGF-C and VEGF-D expression with varying intensities. VEGF-C expression was associated with histological grade. Strong expression of VEGF-D was significantly associated with lymph node metas- tases and linked to a trend for decreased survival in lymph node-positive patients. EGFR blockade with cetuximab resulted in a significant decrease of VEGF-D expression in vitro and in vivo. CONCLUSION： In conclusion, the expression of VEGF-D in colorectal tumours is significantly associated with lymphatic involvement in CRC patients and such expression might be blocked effectively by cetuximab.     

非小细胞肺癌分子靶向治疗的现状及进展

非小细胞肺癌是一种常见的恶性肿瘤,化学治疗的疗效似已达到平台,而分子靶向治疗以其符合生理、低毒和理论上高效的特点,越来越成为晚期非小细胞肺癌治疗的热点.文章就分子靶向治疗的作用靶点包括表皮生长因子受体、血管内皮因子受体,还有最近发现的EML4-ALK等进行综述,以展示分子靶向药物对于晚期非小细胞肺癌治疗的良好前景.     

结直肠癌患者血清中血管内皮生长因子和一氧化氮表达水平及其临床意义

目的:探讨结直肠癌患者血清中血管内皮生长因子(VEGF)和一氧化氮(NO)表达水平及其临床意义.方法:分别采用酶联免疫吸附测定(ELISA)法和分光光度法检测74例结直肠癌患者术前和45例结直肠腺瘤患者以及40例健康人血清中VEGF和NO的含量.结果:结直肠腺瘤患者血清VEGF和NO含量与健康人无明显差异(P＞0.05);结直肠癌患者血清VEGF和NO表达水平分别较结直肠腺瘤组以及健康人明显增高(P＜0.01),且结直肠癌浸润深度、有无淋巴结转移以及Dukes分期与血清VEGF和NO含量呈明显正相关(r=0.834,P＜0.01).结论:VEGF和NO与结直肠癌的发生发展密切相关,术前检测血清VEGF和NO含量可作为判断结直肠癌浸润转移以及Dukes分期的有效生物学指标.     

Current and emerging therapies in unresectable and recurrent gastric cancer

Gastric cancer is one of the most lethal cancers worldwide despite many advances and options in therapy. As it is often diagnosed at an advanced stage, prognosis is poor with a median overall survival of less than twelve months. Chemotherapy remains the mainstay of treatment for these patients but it confers only a moderate survival advantage. There remains a need for new targeted treatment options and a way to better define patient populations who will benefit from these agents. In the past few years, there has been a better understanding of the biology, molecular profiling, and heterogeneity of gastric cancer. Our increased knowledge has led to the identification of gastric cancer subtypes and to the development of new targeted therapeutic agents. There are now two new targeted agents, trastuzumab and ramucirumab, that have recently been approved for the treatment of advanced and metastatic gastric cancer. There are also many other actively investigated targets, including epidermal growth factor receptor, the phosphatadylinositol 3-kinase/protein kinase B/mammalian target of rapamycin pathway, c-Met, poly ADP-ribose polymerase, and immune checkpoint inhibition. In this review, we discuss the current management of advanced gastric cancer as well as emerging targeted therapies and immunotherapy.     

大肠癌EGFR、HER-2、VEGF表达特点及其对分子靶向治疗的指导意义

目的:探讨大肠癌中表皮生长因子受体(EGFR)、人类表皮生长因子受体-2(HER-2)和血管内皮生长因子(VEGF)的表达特点及其对大肠癌分子靶向治疗的指导意义.方法:随机选取2005-05/2009-03中国人民解放军空军总医院普通外科行根治性手术的大肠癌患者78例. 应用免疫组织化学法检测大肠癌肿瘤组织中EGFR、HER-2、VEGF的表达, 并结合其临床病理特点进行回顾性分析.结果:EGF R、HE R-2、VEGF在大肠癌中的阳性表达率依次为38 . 5%( 30 / 78 ) 、53.8%(42/78)、41.0%(32/78). 三者的表达与性别、年龄、肿瘤部位、分化类型无关, 而与肿瘤的大小、侵袭深度和转移密切相关.EGFR与HER-2及VEGF, HER-2与VEGF在大肠癌肿瘤组织中表达呈正相关(r = 0.421,0.484, 0.469, P = 0.019, 0.012, 0.016).结论:EGFR、HER-2、VEGF的表达参与大肠癌的生长、侵袭和转移过程. 三者的联合检测可作为判断大肠癌预后、筛选高危转移患者的有效指标, 同时, 也可用于指导大肠癌的靶向药物治疗.     

Biomarkers of skin toxicity induced by anti-epidermal growth factor receptor antibody treatment in colorectal cancer

Skin toxicity is a common symptom of anti-epidermal rowth factor receptor(EGFR) antibody treatment and is also a predictive marker of its efficacy in colorectal cancer patients. However, severe skin disorders induced by such antibodies negatively impact on the quality of life of patients and decreases drug compliance during treatment. If we can predict the high-risk group susceptible to severe skin toxicity before treatment, we can undertake the early management of any arising skin disorders and formulate a more accurate prognosis for anti-EGFR antibody treatment. Previous studies have identified molecular markers of skin toxicity induced by anti-EGFR antibody, such as EGFR polymorphisms, the expression of inflammatory chemokines and serum levels of EGFR ligands. A clinical trial was undertaken involving the escalation of cetuximab doses, guided by the grade of skin toxicity observed, such as no or low-grade, in metastatic colorectal cancer(the EVEREST study). The dose escalation of cetuximab was confirmed by a safety profile and had the tendency to achieve a higher response rate in KRAS wild-type patients. A large, prospective randomized trial is now ongoing(EVEREST 2) and the results of this trial may contribute to personalized medicine in KRAS wild-type colorectal cancer patients.     

Evidence-based appraisal of the upfront treatment for unresectable metastatic colorectal cancer patients

Colorectal cancer(CRC)is a significant health problem,with around 1 million new cases and 500000 deaths every year worldwide.Over the last two decades,the use of novel therapies and more complex treatment strategies have contributed to progressively increase the median survival of patients with unresectable advanced CRC up to approximately 30 mo.The availability of additional therapeutic options,however,has created new challenges and generated more complicated treatment algorithms.Moreover,several clinically important points are still in debate in first-line,such as the optimal treatment intensity,the most appropriate maintenance strategy,the preferred biologic to be used upfront in patients with KRAS wild-type CRC,and the need for more detailed information on tumor biology.In this moving landscape,this review analyses why the firstline treatment decision is crucial and how the choicemay impact on further treatment lines.In addition,it focuses on results of major phaseⅢrandomized trials.     

血管内皮生长因子-C,-D及其受体3在大肠癌淋巴转移和预后中的价值

目的探讨血管内皮生长因子(VEGF)-C,VEGF-D及其受体3(VEGFR-3)在大肠癌淋巴转移和预后中的价值。方法应用SABC免疫组化和RT-PCR方法检测80例大肠癌和30例大肠正常组织的VEGF-C、VEGF-D、VEGFR-3表达。随访、记录患者的临床病理参数和生存资料,分析其相关性。结果①大肠癌VEGF-C、VEGF-D和VEGFR-3均被染成棕黄褐色,三者蛋白表达阳性率分别为48．8%、56．3%、38．8%,相对表达量为1．09±1．20、1．13±1．09、0．90±1．19；正常大肠组织均无表达。与VEGF-C、VEGF-D和VEGFR-3的mRNA表达一致。②VEGF-C与VEGFR-3表达(P= 0．0069),VEGF-D与VEGFR-3表达间(P=0．0024)存在相关性；VEGF-C与VEGF-D无关。③VEGF-C、VEGF-D、VEGFR-3表达与大肠癌患者的年龄性别、肿瘤部位大小、大体分型、组织学分类、分化程度、肝、肺转移无关,但与Dukes分期(P=0．0234,P=0．0003,P=0．0429)、淋巴结转移(P= 0．0059,P＜0．01,P=0．0068)显著相关；且VEGF-C、VEGFR-3阳性大肠癌患者死亡率明显高于阴性患者(P=0．0374,P=0．0127),生存期明显短于阴性患者(P＜0．01,P＜0．01),VEGF-D则与预后无关。结论大肠癌细胞可分泌淋巴管生成因子VEGF-C、VEGF-D及其受体VEGFR-3,后者通过VEGF-C、-D/VEGFR-3信号通路诱导淋巴管内皮细胞新生和淋巴管生成,从而促进淋巴结转移和肿瘤生长；VEGF-C、VEGF-D、VEGFR-3可作为大肠癌的淋巴管生成的分子表型和淋巴转移及预后判断的重要指标。     

大肠癌EGFR拮抗剂靶向治疗的进展与思考

分子靶向治疗为大肠癌的治疗提供了新的手段,它能够特异性地作用于肿瘤发生发展中起关键作用的靶分子及其调控的信号传导通路,从而达到治疗肿瘤的目的。在肿瘤分子靶向治疗的临床试验中,表皮生长因子受体（EGFR）拮抗剂对大肠癌的药物治疗已经显示出了潜在的疗效和良好的发展前景。本文拟就其理论基础及临床研究进展做一回顾。     

非小细胞肺癌EGFR靶向治疗的研究进展

肺癌是目前世界上发病率和病死率最高的癌症,其中非小细胞肺癌(NSCLC)占肺癌的85％以上.近10年来,随着对肿瘤生物学的深入研究,作为NSCLC治疗靶点的多个基因突变已被识别,其中表皮生长因子受体(EGFR)基因的突变频率最高,因此,EGFR基因的靶向治疗也逐渐成为NSCLC治疗的主力军.本文将就目前NSCLC中的EGFR基因突变及其靶向治疗药物进行简要阐述.     

Strategies to overcome resistance to epidermal growth factor receptor monoclonal antibody therapy in metastatic colorectal cancer

Administration of monoclonal antibodies(mAbs)against epidermal growth factor receptor(EGFR)such as cetuximab and panitumumab in combination with conventional chemotherapy substantially prolongs survival of patients with metastatic colorectal cancer(mCRC).However,the efficacy of these mAbs is limited due to genetic variation among patients,in particular K-ras mutations.The discovery of K-ras mutation as a predictor of non-responsiveness to EGFR mAb therapy has caused a major change in the treatment of mCRC.Drugs that inhibit transformation caused by oncogenic alterations of Ras and its downstream components such as BRAF,MEK and AKT seem to be promising cancer therapeutics as single agents or when given with EGFR inhibitors.Although multiple therapeutic strategies to overcome EGFR mAb-resistance are under investigation,our understanding of their mode of action is limited.Rational drug development based on stringent preclinical data,biomarker validation,and proper selection of patients is of paramount importance in the treatment of mCRC.In this review,we will discuss diverse approaches to overcome the problem of resistance to existing anti-EGFR therapies and potential future directions for cancer therapies related to the mutational status of genes associated with EGFRRas-ERK and PI3K signalings.     

晚期胃癌分子靶向治疗的现状及其发展趋势

胃癌死亡率占全球第2位.目前,化疗仍是晚期胃癌的主要治疗手段.尽管新药联合化疗在一定水平改善了患者的生存,但晚期胃癌中位生存仍不尽人意.迫切需要新的治疗手段改善患者的生存.随着胃癌分子生物学研究的不断深入,针对肿瘤细胞生长、凋亡、侵袭浸润以及血管生成等分子靶点提出的分子靶向治疗成为胃癌综合治疗的热点.本文将对近几年报道...