Therapeutic targeting of receptor tyrosine kinases in lung cancer

Lung cancer is a difficult illness with a poor overall survival. Even though combination strategies with chemotherapy, radiation therapy and surgery have all been utilised, the overall outcome for this disease continues to be relatively disappointing. In order to make a difference in the treatment of lung cancer, novel therapeutics will have to be developed. Through basic biological studies, a number of receptor tyrosine kinases have been implicated in the pathogenesis and progression of lung cancer. In this review, the authors summarise the mechanisms of several major receptor tyrosine kinases in lung cancer, especially epidermal growth factor receptor, Her2/neu, MET, vascular endothelial growth factor and KIT. The biology associated with these receptors is described, and the various novel therapeutic inhibitory strategies that are ongoing in preclinical and clinical studies for lung cancer are detailed. Through understanding of receptor tyrosine kinases and the utilisation of specific inhibitors, it is hopeful that a dramatic impact will be made on the biology and therapy for lung cancer.     

Therapeutic targeting of receptor tyrosine kinases in lung cancer

Lung cancer is a difficult illness with a poor overall survival. Even though combination strategies with chemotherapy, radiation therapy and surgery have all been utilised, the overall outcome for this disease continues to be relatively disappointing. In order to make a difference in the treatment of lung cancer, novel therapeutics will have to be developed. Through basic biological studies, a number of receptor tyrosine kinases have been implicated in the pathogenesis and progression of lung cancer. In this review, the authors summarise the mechanisms of several major receptor tyrosine kinases in lung cancer, especially epidermal growth factor receptor, Her2/neu, MET, vascular endothelial growth factor and KIT. The biology associated with these receptors is described, and the various novel therapeutic inhibitory strategies that are ongoing in preclinical and clinical studies for lung cancer are detailed. Through understanding of receptor tyrosine kinases and the utilisation of specific inhibitors, it is hopeful that a dramatic impact will be made on the biology and therapy for lung cancer.     

Inhibition of receptor tyrosine kinase-based signal transduction as specific target for cancer treatment

Every cell in a multicellular organism receives signals from the extracellular matrix and neighboring cells. These signals are transmitted, via transmembrane receptors and cascade proteins of the intracellular message system, inside the cell and often to the nucleus, regulating almost every physiological function of the cell. Protein tyrosine kinases constitute a family of receptors that regulate major cellular events, such as cell proliferation, differentiation, cell adhesion and apoptosis. Mutant tyrosine kinases and/or their aberrant activity are associated with human cancer and other hyper-proliferative diseases. Strategies for inhibition of aberrant tyrosine kinase activity, such as antisense oligonucleotides, antigenic stimulation and small molecular inhibitors have been developed. STI571, a phenylaminopyrimidine derivative, is considered to be the pioneer of the small molecular inhibitors available to date. It is a successful tyrosine kinase inhibitor, which is currently approved and used for the treatment of chronic myelogenous leukemia and gastrointestinal tumors. In this article we review the mechanisms of cell signaling, the signal transduction pathways related to tyrosine kinases, their relationship with cancer, and the strategies developed to inhibit the aberrant tyrosine kinase receptor-based signal transduction. Drug resistance and future perspectives for combination therapies are also discussed.     

紫杉醇联合表阿霉素双周方案治疗转移性乳腺癌32例

目的观察紫杉醇联合表阿霉素(TE)双周方案治疗转移性乳腺癌的近期疗效与毒副反应。方法32例转移性乳腺癌患者采用TE方案化疗,表阿霉素40mg/(m2.d)第1、2天静脉滴注,紫杉醇85mg/m2第3天静脉滴注,14天为一周期,完成2～4个周期,评价疗效和毒副反应。结果CR5例,PR19例,NC8例,无PD,有效率(RR)为75.00%,其中初治组有效率为91.67%,复治组为65.00%(P<0.05),差异有统计学意义,初治组有效率高于复治组。主要剂量限制性毒性为骨髓抑制,Ⅲ～Ⅳ度骨髓抑制发生率为40.63%(13/32),所有患者均需要使用G-CSF支持治疗。结论TE双周方案治疗转移性乳腺癌疗效好,毒副反应可耐受,是治疗晚期乳腺癌较好的方案。     

First-line combination chemotherapy with mitoxantrone and cyclophosphamide in advanced breast cancer

Summary In this study, 30 evaluable patients with advanced carcinoma of the breast were treated with cyclophosphamide 600 mg/m² i.v. followed one day later with mitoxantrone (Novantrone®; dihydroxyanthracenedione) 16 mg/m² i.v. Drug treatment was repeated every 3–4 weeks, for a maximum of 12 cycles. The overall response rate was 43%; five of 30 patients (16%) attained a complete remission, and eight of 30 (27%) had a partial remission. Median response duration was 12+ months. The greater number of responses was seen in skin and soft tissues. Hematologic toxicity was limiting with 75% of patients experiencing substantial-severe leukopenia. Clinically evident heart failure developed in one patient; in three other patients there was minor-moderate alteration of cardiac function during mitoxantrone-cyclophosphamide therapy. Based on these data, it is believed that this regimen may provide significant long-lasting palliation in patients with advanced breast cancer.     

Safety of neoadjuvant chemotherapy for the treatment of breast cancer

Introduction: Preoperative systemic therapy (PST) including neoadjuvant chemotherapy (NAC) in breast cancer (BC) is used nowadays on a large scale especially in aggressive BC subtypes. The use of NAC in BC may be associated with some safety issues and hazards including possible increased rate of locoregional recurrence, inadequate staging with subsequent over or under-treatment, and surgical complications.

Areas covered: This review article aims to discuss these concerns and to clarify the adequate steps and procedures needed to increase safety and alleviate the possible drawbacks of NAC. The author will discuss the adequate and meticulous technical procedures needed to stage and localize the breast tumor, detect any affected axillary lymph node, improve the accuracy and safety of doing sentinel lymph node biopsy (SLNB) after NAC, estimate the tumor response to NAC to determine the extent of surgery, and enhance the precise documentation of pCR.

Expert opinion: The use of breast MRI, image-detectable clips in the tumor bed, dual technique during SLNB, and target axillary dissection are among the required steps to maintain safety. In the future, ongoing prospective trials will allow us to select patients who can safely avoid breast and/or axillary surgery after systemic therapy.     

蒽环类联合紫杉类药物新辅助化疗方案治疗乳腺癌的临床疗效研究

目的研究蒽环类联合紫杉类化疗药新辅助化疗方案治疗乳腺癌的临床疗效和安全性。方法选取2012年1月至2013年6月我院收治的76例乳腺癌患者,依据治疗方案分为观察组和对照组,每组均38例。收集患者年龄、家族史、肿瘤转移等一般临床资料,对比分析两组患者治疗后临床疗效和药物不良反应情况,对比两组患者治疗后总体生存数据。结果观察组的总体治疗有效率(92.1%)显著高于对照组(71.0%),差异有统计学意义(P<0.05)。两组患者用药不良反应发生率比较差异无统计学意义(P>0.05)。随访生存分析结果显示,治疗后观察组患者的总体生存时间为(59.1±4.3)个月,显著长于对照组的(51.3±4.5)个月,差异有统计学意义(P<0.05)。结论蒽环类联合紫杉类化疗药物的新辅助化疗方案治疗乳腺癌疗效较好,安全性高,可提高患者预后生存时间。     

药物联合使用在高耐药性乳腺癌化学治疗中的应用价值

目的 探讨药物联合使用在高耐药性乳腺癌化学治疗中的应用价值.方法 晚期高耐药性乳腺癌患者140例根据随机数字表法分为研究组与对照组,各70例,2组都选择常规NP方案(长春瑞滨+顺铂)进行化疗,对照组口服他莫昔芬10 mg/d,2次/d,研究组在对照组治疗的基础上口服托瑞米芬30 mg/d,1次/d.比较2组的疗效、生活质量评分、病死率及平均生存时间.结果 治疗后研究组完全缓解35例,部分缓解15例,有效率71.4％,对照组完全缓解15例,部分缓解20例,有效率50.0％.研究组的有效率明显高于对照组(x2=4.092,P＜0.05).2组治疗后生活质量评分高于治疗前[研究组为(90±6)分比(76 ±5)分,t=15.978,P＜0.05;对照组为(84 ±5)分比(75 ±4)分,t=8.772,P＜0.05],研究组治疗后的生活质量评分明显高于对照组(t=7.093,P＜0.05).2组病死率差异无统计学意义(P＞0.05),研究组的平均生存时间明显高于对照组[(42±5)个月比(37 ±5)个月,t=5.091,P＜0.05].结论 在高耐药性乳腺癌化学治疗中,内分泌药物联合使用能促进近期疗效的提高,提高患者的生存期间与延长生存时间.     

Luteininzing hormone releasing hormones analogs in combination with tamoxifen for the adjuvant treatment of premenopausal women with hormone receptor positive breast cancer

Introduction: The role of ovarian function suppression (OFS) through luteinizing hormone-releasing hormone agonists (LHRHa) in addition to tamoxifen has been questioned until recently. In 2015, two large clinical trials led to a paradigm shift in the adjuvant endocrine treatment of premenopausal women, introducing the use of LHRHa plus tamoxifen (or aromatase inhibitor, AI) into current clinical practice.

Areas covered: The present review aims to provide an in-depth overview of the role of LHRHa+tamoxifen for the adjuvant treatment of premenopausal women with hormone receptor positive breast cancer (HR+BC).

Expert opinion: The addition of LHRHa to endocrine treatment (either tamoxifen or AI) is effective in premenopausal women who are at high risk of relapse. To date, no clear recommendations are available for the choice between LHRHa+tamoxifen and LHRH+AI. Although recent data showed better DFS with LHRHa+AI, other issues should be considered: 1) approximately 20 out of 100 women do not reach complete OFS with LHRHa+AI; 2) there is no extended endocrine therapy option that can be applied to women who received 5 years of LHRHa+AI and remained premenopausal at the end of the fifth year. Long-term results of the SOFT-TEXT study are needed to establish if LHRHa+AI is superior to LHRHa+tamoxifen.     

西妥昔单抗联合化疗治疗消化系统肿瘤的临床研究

目的观察西妥昔单抗联合化疗治疗消化系统肿瘤的疗效及不良反应。方法回顾性分析17例接受西妥昔单抗联合化疗治疗的消化系统肿瘤患者的资料,对其进行疗效评价及安全性分析。合并的化疗方案主要有以奥沙利铂或伊立替康为主的联合化疗以及伊立替康单药化疗。结果全组可评价疗效者13例,有效率（RR）为46.2%,疾病控制率（DCR）为76.9%,中位疾病进展时间（TTP）4.0个月。一线治疗6例,RR为66.7%,DCR为83.3%,中位TTP 4.8个月。13例有8例为结直肠癌,RR为50%,DCR为87.5%,中位TTP 5.0个月,其中一线治疗3例全部获得PR。痤疮样皮疹发生率为52.9%,但未显示出皮疹与有效率的相关性。结论西妥昔单抗联合化疗治疗消化系统肿瘤安全有效,尤其一线治疗效果更佳,值得进一步扩大样本研究。     

Inhibitors of tyrosine kinases in the treatment of psoriasis

Psoriasis is a heterogenous skin disease, characterized by epidermal hyperproliferation, abnormal keratinization and inflammation. The heterogeneity of the disease results probably from the interaction of multiple gene abnormalities with environmental factors. The new approaches to drug design have become refocused to the emerging understanding of the role of signaling pathways in health and disease. Protein tyrosine kinases (PTKs) regulate cell proliferation, differentiation and immune processes. Uncontrolled signaling from receptor and intracellular tyrosine kinases can lead to numerous proliferative diseases: cancer, leukemia, restenosis and psoriasis. Identification of PTKs that play a key role in a defined disease can lead to a selective drug. The balance of signals which regulate the homeostasis of normal epidermis is altered in psoriasis. Several lines of evidence suggest a role for the EGF receptor system in this process. Therefore, blockers of the EGFR kinase were suggested as potent antipsoriasis agents. PTK inhibitors from the tyrphostin family were found to block EGF - dependent cell proliferation. AG 1571 (SU 5271) potently inhibits ligand-induced autophosphorylation of EGF-R, downstream signal transduction events, DNA replication and cell cycle progression at micromolar concentrations, as well as proliferation of keratinocytes isolated from psoriatic lesions in excellent correlation with its EGFR kinase inhibitory activity in these cells. AG 1571 (SU 5271) has been in clinical trials by SUGEN Inc. since early 1997. Overexpression of the EGFR is the hallmark of most epithelial cancers. Therefore one can view blockers of the EGFR kinase as becoming universal inhibitors. Tyrphostins are the first signal transduction agents to be used in the clinic. This article summarizes recent progress in the development of PTK inhibitors in the treatment of psoriasis.     

Site-directed irreversible inhibitors of the erbB family of receptor tyrosine kinases as novel chemotherapeutic agents for cancer

The erbB family of tyrosine kinases represents a versatile set of four plasma membrane receptors that possesses enormous diversity in signaling capability. The rationale to target this receptor system as an approach to cancer chemotherapy has continued to become more compelling with time. Both preclinical and clinical data strongly support the involvement of these receptors in the formation and progression of human cancers as well as establish a high correlation in cancer patients between receptor/ligand expression and poor prognosis. During the past 4 years significant progress has been made in the area of epidermal growth factor receptor tyrosine kinase inhibitors and new structural classes have emerged that exhibit enormous improvements with regard to potency, specificity, and in vitro and in vivo efficacy. More recent advancements in this field have resulted in the discovery of very specific, irreversible inhibitors of the erbB family that provide unique pharmacological properties and exceptional efficacy. The in vivo performance of these modern kinase inhibitors has improved to the point where several compounds are either in clinical trials or very near to that point in their development. This article will provide a brief biological review of the erbB family and the justification for targeting this receptor family in cancer therapeutics, and then highlight some of the more promising kinase antagonists with emphasis on irreversible inhibitors.     

Investigational ErbB-2 tyrosine kinase inhibitors for the treatment of breast cancer

Introduction: ErbB2 overexpression and/or gene amplification is present in 20% of all breast cancers and characterizes an aggressive form of this disease. Despite the availability of several active drugs that have yielded substantial survival improvements, most patients with ErbB2-positive metastatic disease will develop tumor progression, either because of primary or acquired resistance. Therefore, research has focused on drugs that can more efficiently interfere with ErbB2 and with other members of the epidermal growth factor receptor family.

Areas covered: This review focuses on those investigational drugs that inhibit ErbB2 tyrosine kinase activity (TKIs) for treating breast cancer.

Expert opinion: ErbB-targeting TKIs show encouraging activity in patients with ErbB-positive tumors that are resistant to conventional ErbB-therapies (mostly trastuzumab), confirming pre-clinical observations. Efficient interference with the ErbB-network signaling implies also a potential use in ErbB2-normal tumors, where the phenotype is sustained by ErbB-aberrant signaling. Finally, early data suggests that ErbB-targeting TKIs could be active in treating patients with activating ErbB2 mutations. Ongoing and future research efforts should elucidate what is, according to the peculiarities of these compounds, their positioning in the treatment of women with breast cancer.     

Docetaxel/trastuzumab combination therapy for the treatment of breast cancer

Trastuzumab is a humanised monoclonal antibody that targets the extra cellular domain of human epidermal growth factor receptor-2 (HER-2), which is overexpressed in ~ 20% of human breast cancers. Clinical benefit has been shown in breast cancer patients with HER-2 amplification or overexpression when trastuzumab is used alone or in combination with chemotherapy. Docetaxel is one of the most potent chemotherapy agents in the treatment of patients with metastatic and early-stage breast cancer. The rationale for combining these two drugs is based not only on preclinical synergic data, but also on expanding clinical results. This article reviews the results of trials investigating this two-drug combination, as well as the triple combinations including docetaxel and trastuzumab with platinum salts. These combinations appear to be amongst the most active therapies for the treatment of patients with HER-2-positive breast cancer in metastatic and potentially adjuvant settings.     

射频热疗联合介入化疗治疗晚期大肠癌疗效分析

目的 观察射频热疗联合介入持续动脉化疗治疗晚期大肠癌的临床初步疗效。方法 对20例局部复发和伴有肝、肺、骨、腹腔、盆腔及腹股沟淋巴结转移的晚期大肠癌患者经射频热疗法联合供养靶动脉介入灌注化疗。每例患者至少进行2个周期的介入化疗联合热疗。化疗方案为第1～3天亚叶酸钙200mg／m^2静脉滴注；第1天顺氯氨铂80mg／m^2，第1～3天如肾功能改变则改用鬼臼乙叉苷60mg／m^2动脉滴注；5-氟尿嘧啶2500mg／m^2加入超液化碘油10-30ml中进行肝动脉灌注栓塞。热疗频率40．68MHz，电容式加热，电极直径20-25cm，入射功率500-800W，反射功率20-40W。插管化疗第2天开始进行热疗，每72小时1次，每次50-0min，每疗程化疗配合4～8次热疗。结果 病灶近期疗效以CT或B超检查结果作为评价标准，完全缓解0例，部分缓解14例，总有效率为70．0％。患者化疗未出现严重不良反应。热疗不良反应为局部疼痛和脂肪硬结，不需特殊处理。结论 射频热疗联合介入持续动脉化疗治疗晚期大肠癌安全、有效。     

Docetaxel/trastuzumab combination therapy for the treatment of breast cancer

Trastuzumab is a humanised monoclonal antibody that targets the extra cellular domain of human epidermal growth factor receptor-2 (HER-2), which is overexpressed in approximately 20% of human breast cancers. Clinical benefit has been shown in breast cancer patients with HER-2 amplification or overexpression when trastuzumab is used alone or in combination with chemotherapy. Docetaxel is one of the most potent chemotherapy agents in the treatment of patients with metastatic and early-stage breast cancer. The rationale for combining these two drugs is based not only on preclinical synergic data, but also on expanding clinical results. This article reviews the results of trials investigating this two-drug combination, as well as the triple combinations including docetaxel and trastuzumab with platinum salts. These combinations appear to be amongst the most active therapies for the treatment of patients with HER-2-positive breast cancer in metastatic and potentially adjuvant settings.     

Novel combination chemotherapy in the treatment of non-small cell lung cancer

Treatment of patients with advanced non-small cell lung cancer (NSCLC) remains a vexing problem and long-term survival beyond 5 years is extremely rare. Five new agents, paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan, have been introduced for the treatment of NSCLC and investigated extensively both preclinically and clinically. Monotherapy with one of these agents has produced survival benefits over the best supportive care in Phase III studies. Combination chemotherapy with a new agent and platinum produced a higher response rate than conventional cisplatin-based chemotherapy and improved survival was observed in some randomised trials. There was little difference in efficacy and toxicity between the chemotherapeutic regimens with a new agent and a platinum in Phase III trials, suggesting the clinical utility of these regimens is similar. Many trials have focused on regimens containing two new agents, with or without platinum. Preliminary results of Phase III trials of three drug combinations versus two drug combinations suggested the former to be more promising, in terms of response rates and survival. Whether the era of platinum-based chemotherapy in the treatment of NSCLC should continue or not must be determined by Phase III trials, evaluating the use of a platinum agent with one of the new agent combinations. These aggressive chemotherapeutic combinations will hopefully improve survival and quality of life for patients with advanced NSCLC.     

Novel combination chemotherapy in the treatment of non-small cell lung cancer

Treatment of patients with advanced non-small cell lung cancer (NSCLC) remains a vexing problem and long-term survival beyond 5 years is extremely rare. Five new agents, paclitaxel, docetaxel, vinorelbine, gemcitabine and irinotecan, have been introduced for the treatment of NSCLC and investigated extensively both preclinically and clinically. Monotherapy with one of these agents has produced survival benefits over the best supportive care in Phase III studies. Combination chemotherapy with a new agent and platinum produced a higher response rate than conventional cisplatin-based chemotherapy and improved survival was observed in some randomised trials. There was little difference in efficacy and toxicity between the chemotherapeutic regimens with a new agent and a platinum in Phase III trials, suggesting the clinical utility of these regimens is similar. Many trials have focused on regimens containing two new agents, with or without platinum. Preliminary results of Phase III trials of three drug combinations versus two drug combinations suggested the former to be more promising, in terms of response rates and survival. Whether the era of platinum-based chemotherapy in the treatment of NSCLC should continue or not must be determined by Phase III trials, evaluating the use of a platinum agent with one of the new agent combinations. These aggressive chemotherapeutic combinations will hopefully improve survival and quality of life for patients with advanced NSCLC.