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.     

Challenge and countermeasures for EGFR targeted therapy in non-small cell lung cancer

Lung cancer causes the highest mortality compared to other cancers in the world according to the latest WHO reports. Non-small cell lung cancer (NSCLC) contributes about 85% of total lung cancer cases. An extensive number of risk factors are attributed to the progression of lung cancer. Epidermal growth factor receptor (EGFR), one of the most frequently mutant driver genes, is closely involved in the development of lung cancer through regulation of the PI3K/AKT and MAPK pathways. As a representative of precision medicine, EGFR-tyrosine kinase inhibitors (TKIs) targeted therapy significantly relieves the development of activating mutant EGFR-driven NSCLC. However, treatment with TKIs facilitates the emergence of acquired resistance that continues to pose a significant hurdle with respect to EGFR targeted therapy. In this review, the development of current approved EGFR-TKIs as well as the related supporting clinical trials are summarized and discussed. Mechanisms of action and resistance were addressed respectively, which serve as important guides to understanding acquired resistance. We also explored the corresponding combination treatment options according to different resistance mechanisms. Future challenges include more comprehensive characterization of unclear resistance mechanisms in different populations and the development of more efficient and precision synthetic therapeutic strategies.     

非小细胞肺癌靶向治疗的临床前研究进展

针对表皮生长因子受体（EGFR）和血管生成（angiogenesis）信号通路的靶向治疗已经在晚期非小细胞肺癌的治疗上取得成功,但由于抗药性的存在,大多数晚期患者的生存时间仍然提高有限。继发性的EGFR T790M突变和原癌基因肝细胞生长因子受体（MET）的扩增被鉴定为两种主要的抗药机制。最近转化生长因子-β（TGF-β）/白介素-6信号通路被报道能介导选择性和适应性地对erlotinib的抗药。另一方面,Kras突变所致肺癌的靶向治疗方面也取得了一些进展。双重抑制磷脂酰肌醇3-激酶（PI3K）和促分裂素原活化蛋白激酶激酶（MEK）信号通路可导致Kras突变肿瘤的显著消退,联合抑制SRC、PI3K和MEK可使丝氨酸/苏氨酸蛋白激酶11（Lkb1）缺失,Kras突变的肺癌小鼠的肿瘤明显消退,抑制核因子-κB（NF-κB）信号通路导致p53缺失,Kras突变的肿瘤发展显著减慢。这些发现都为发展非小细胞肺癌患者的靶向治疗提供了有力的支持。     

Epigenetic therapy approaches in non-small cell lung cancer: Update and perspectives

Non-small cell lung cancer (NSCLC) still constitutes the most common cancer-related cause of death worldwide. All efforts to introduce suitable treatment options using chemotherapeutics or targeted therapies have, up to this point, failed to exhibit a substantial effect on the 5-year-survival rate. The involvement of epigenetic alterations in the evolution of different cancers has led to the development of epigenetics-based therapies, mainly targeting DNA methyltransferases (DNMTs) and histone-modifying enzymes. So far, their greatest success stories have been registered in hematologic neoplasias. As the effects of epigenetic single agent treatment of solid tumors have been limited, the investigative focus now lies on combination therapies of epigenetically active agents with conventional chemotherapy, immunotherapy, or kinase inhibitors. This review includes a short overview of the most important preclinical approaches as well as an extensive discussion of clinical trials using epigenetic combination therapies in NSCLC, including ongoing trials. Thus, we are providing an overview of what lies ahead in the field of epigenetic combinatory therapies of NSCLC in the coming years.     

Drug-induced cell cycle perturbation in chemotherapy of patients with non-small cell lung cancer

To observe in vivo cell cycle perturbation in the chemotherapy of lung cancer, tumour cell kinetics during the first course of chemotherapy were measured in seven patients with histologically-verified non-small cell lung cancer. The tumour cells were aspirated from six lymph nodes and one subcutaneous nodule both prior to treatment and twice weekly after the administration of chemotherapeutic agents. The nuclear DNA content of aspirated tumour cells was measured with a scanning microdensitometer at a wavelength of 550 nm after the modified Feulgen reaction. The cell population in cell cycle was estimated with a cumulated percentage scale. Marked cell cycle perturbation occurred within one week after initiation of chemotherapy. There was a decrease in the G1 cell population, from 70.6 +/- 9.1% to 26.1 +/- 11.4%, and a corresponding increase of cells in G2-M phase, from 21.4 +/- 8.7% to 63.7 +/- 10.0%. The proportion of cells in S phase was slightly increased from 8.0 +/- 1.5% to 10.1 +/- 3.2% during this period. The degree of cell cycle changes was unrelated to the clinical response to chemotherapy.     

Gemcitabine in the first and second-line chemotherapy of advanced non-small cell lung cancer

Aim of this study was to estimate efficacy of gemcitabine in first and the second-line chemotherapy for patients with advanced non-small cell lung cancer (stage III and IV). In first-line chemotherapy, 120 patients were treated with different chemotherapy regimens. Fifty-nine patients were treated with gemcitabine / cisplatin (PG), 41 with cisplatin / etoposide (PE) and 20 with mitomycin / ifosfamide / cisplatin (MIC). Forty patients, unsuccessfully treated with PE and MIC in first-line therapy were treated with PG (24 pts) and with best supportive care (BSC) (16 pts). In first-line therapy PG was superior to PE and MIC protocol (mean survival (MS) 10 vs. 7 vs. 8.5 months). Response rate (RR) for PG in first-line therapy was 46% and 21% in second-line. We showed also significantly better survival in patients treated with PG in second-line chemotherapy comparing to best supportive care (MS 9 vs. 5.5 months). Toxic side effects for combination PG was acceptable. This study confirmed that PG combination is safe and effective as first and second-line chemotherapy for patients with advanced non-small cell lung cancer.     

Controversies in the management of advanced non-small cell lung cancer: maintenance therapy

The majority of patients with non-small cell lung (NSCLC) present with advanced, metastatic disease at the time of diagnosis. The current state of the art for the management of this condition is first- and second-line chemotherapy (CT), along with appropriate supporting care measures, which are supposed to alleviate symptoms and to improve survival. During the last years, maintenance therapy (MT) was included in the therapeutic algorithm for these patients. MT could be defined as continuation of an active treatment until disease progression in patients who demonstrated a non-progressing status following induction chemotherapy. Despite the results of several randomized trials showing a significant benefit by using this approach, the strategy is far from being universally accepted. The internationally recognized guidelines provide different recommendation when it comes to this topic, while some major drawbacks in the design of the positive clinical trials may have distorted the relevance of the communicated data. This paper aimed to review the most contentious aspects which should be considered while contemplating the use of MT in the daily clinical practice.     

The role of adjuvant chemotherapy in the treatment of non-small cell lung cancer

Postoperative treatments for lung cancer have been evaluated for more than two decades, but in the majority of the studies (especially until 1990) no significant effect on survival has been shown. In 1995, a meta-analysis of eight cisplatin-based adjuvant chemotherapy trials with NSCLC showed a 13% reduction in the risk of death (P=0.08) and 5% benefit in 5-year survival. Among four positive trials (IALT, JBR10, ANITA and CALGB study) the absolute increase in the 5-year survival rates by adjuvant chemotherapy ranged from 4% to 15%, and the hazard ratios for death ranged from 0.6 to 0.86. The author analyzes the most important studies. Conclusion: adjuvant chemotherapy after complete resection of NSCLC can be considered as a new standard of care in patients with good performance status. Patients should receive 4 cycles of platina-based chemotherapy beginning 4-8 weeks after surgery. Future perspectives: optimization of chemotherapy regimens including targeted therapy (such as EGFR inhibitors, angiogenesis inhibitors, anti-EGFR monoclonal antibodies). Further progress is anticipated through the integration of chemopreventive agents into the adjuvant treatment.     

Financial aspects of targeted therapy of lung cancer as compared to conventional chemotherapy

Lung cancer is the leading cause of cancer death worldwide, and it is responsible for 20-25% of all cancer deaths. In Hungary, more than 4,000 lung cancer patients receive chemotherapy every year, and of them 3,000 suffer from non-small cell lung cancer. Despite the rapid development in antitumor treatment options, the response rates of chemotherapies in non-small cell lung cancer still remain between 15-35%. Recently, EGFR tyrosine kinase inhibitor therapy has been introduced with a response rate of 15% when used in unselected patients. However, this ratio may increase up to 70% when only patients with tumors containing EGFR mutation are treated. Therefore, results of translational research that could help pulmonologists and oncologists to apply tailored therapy in lung cancer patients are of great importance. The purpose of our work was to establish a model in order to study the relevance of immunohistochemical and molecular biological analyses of tumor specimens in treatment and patient selection, and to investigate their cost-sparing effects. We concluded that the most cost-effective type of patient selection could be achieved with EGFR mutation status analysis of the tumor tissue. Our results may help to determine the most cost-effective way of patient selection in case of non-small cell lung cancer patients requiring second line therapy; moreover, they might serve as a basis for further economic analyses.     

Targeted therapy for LIMD1-deficient non-small cell lung cancer subtypes

An early event in lung oncogenesis is loss of the tumour suppressor gene LIMD1 (LIM domains containing 1); this encodes a scaffold protein, which suppresses tumorigenesis via a number of different mechanisms. Approximately 45% of non-small cell lung cancers (NSCLC) are deficient in LIMD1, yet this subtype of NSCLC has been overlooked in preclinical and clinical investigations. Defining therapeutic targets in these LIMD1 loss-of-function patients is difficult due to a lack of ‘druggable’ targets, thus alternative approaches are required. To this end, we performed the first drug repurposing screen to identify compounds that confer synthetic lethality with LIMD1 loss in NSCLC cells. PF-477736 was shown to selectively target LIMD1-deficient cells in vitro through inhibition of multiple kinases, inducing cell death via apoptosis. Furthermore, PF-477736 was effective in treating LIMD1^−/− tumours in subcutaneous xenograft models, with no significant effect in LIMD1^+/+ cells. We have identified a novel drug tool with significant preclinical characterisation that serves as an excellent candidate to explore and define LIMD1-deficient cancers as a new therapeutic subgroup of critical unmet need.Subject terms: Targeted therapies, Non-small-cell lung cancer     

Addition of bevacizumab to chemotherapy in advanced non-small cell lung cancer: a systematic review and meta-analysis

IntroductionRecently, studies have demonstrated that the addition of bevacizumab to chemotherapy could be associated with better outcomes in patients with advanced non-small cell lung cancer (NSCLC). However, the benefit seems to be dependent on the drugs used in the chemotherapy regimens. This systematic review evaluated the strength of data on efficacy of the addition of bevacizumab to chemotherapy in advanced NSCLC.MethodsPubMed, EMBASE, and Cochrane databases were searched. Eligible studies were randomized clinical trials (RCTs) that evaluated chemotherapy with or without bevacizumab in patients with advanced NSCLC. The outcomes included overall survival (OS), progression-free survival (PFS), response rate (RR), toxicities and treatment related mortality. Hazard ratios (HR) and odds ratios (OR) were used for the meta-analysis and were expressed with 95% confidence intervals (CI).ResultsWe included results reported from five RCTs, with a total of 2,252 patients included in the primary analysis, all of them using platinum-based chemotherapy regimens. Compared to chemotherapy alone, the addition of bevacizumab to chemotherapy resulted in a significant longer OS (HR 0.89; 95% CI 0.79 to 0.99; p = 0.04), longer PFS (HR 0.73; 95% CI 0.66 to 0.82; p<0.00001) and higher response rates (OR 2.34; 95% CI 1.89 to 2.89; p<0.00001). We found no heterogeneity between trials, in all comparisons. There was a slight increase in toxicities in bevacizumab group, as well as an increased rate of treatment-related mortality.ConclusionsThe addition of bevacizumab to chemotherapy in patients with advanced NSCLC prolongs OS, PFS and RR. Considering the toxicities added, and the small absolute benefits found, bevacizumab plus platinum-based chemotherapy can be considered an option in selected patients with advanced NSCLC. However, risks and benefits should be discussed with patients before decision making.     

Prohibitin对非小细胞肺癌细胞增殖和凋亡的影响

目的:研究Prohibitin对非小细胞肺癌株A549和NCI-H460细胞增殖和凋亡的影响.方法:将针对Prohibitin的特异性的干扰片段瞬时转染非小细胞肺癌A549和NCI-H460细胞株,以瞬时转染与Prohibitin没有同源性的干扰片段的细胞作为阴性对照,通过免疫蛋白印迹检测各组细胞Prohibitin和Survivin蛋白的表达情况,通过MTT法检测各组细胞的增殖情况,通过流式仪检测各组细胞的凋亡率.结果:针对Prohibitin基因设计的siRNA片段特异性地沉默该基因的表达,与对照组相比较,干扰组的细胞的增殖活性明显增强.同时与凋亡密切相关的Survivin的表达在沉默掉prohibitin后,在A549和NCI-H460中分别降低了46.3%和54.5%.而干扰prohibitin后导致A549细胞的凋亡率上升了约2%.结论:Prohibitin能显著抑制非小细胞肺癌A549和NCI-H460细胞的增殖,而对凋亡的影响可能并不是通过survivin介导的.     

抗-VEGF和抗-EGFR药物在进展期非小细胞肺癌治疗中的应用

化疗对非小细胞肺癌的疗效已到达平台期,研发更为有效、易耐受的治疗策略势在必行.肿瘤生物学分子机制研究孕育了分子靶向治疗.VEGF、EGFR相关信号通路在肿瘤发生、发展中发挥重要作用,是抗肿瘤药物的重要分子靶点.贝伐单抗联合化疗和小分子酪氨酸激酶抑制剂(埃罗替尼和吉非替尼)分别成为非小细胞肺癌的一、二线治疗方案.本文将综述多种抗-VEGF和抗-EGFR新药在进展期非小细胞肺癌治疗中的临床应用.     

Tumor-infiltrating lymphocytes predict response to chemotherapy in patients with advance non-small cell lung cancer

Accumulating preclinical evidence suggests that anticancer immune responses contribute to the success of chemotherapy. The predictive significance of tumor-infiltrating lymphocytes (TILs) for response to neoadjuvant chemotherapy in non-small cell lung cancer (NSCLC) remains unknown. The aim of this study was to investigate the prognostic and predictive value of TIL subtypes in patients with advanced NSCLC treated with platinum-based chemotherapy. In total, 159 patients with stage III and IV NSCLC were retrospectively enrolled. The prevalence of CD3(+), CD4(+), CD8(+) and Foxp3(+) TILs was assessed by immunohistochemistry in tumor tissue obtained before chemotherapy. The density of TILs subgroups was treated as dichotomous variables using the median values as cutoff. Survival curves were estimated by the Kaplan-Meier method, and differences in overall survival between groups were determined using the Log-rank test. Prognostic effects of TIL subsets density were evaluated by Cox regression analysis. The presence of CD3(+), CD4(+), CD8(+), and FOXP3(+) TILs was not correlated with any clinicopathological features. Neither the prevalence of TILs nor combined analysis displayed obvious prognostic performances for overall survival in Cox regression model. Instead, higher FOXP3(+)/CD8(+) ratio in tumor sites was an independent factor for poor response to platinum-based chemotherapy in overall cohort. These findings suggest that immunological CD8(+) and FOXP3(+)Tregs cell infiltrate within tumor environment is predictive of response to platinum-based neoadjuvant chemotherapy in advanced NSCLC patients. The understanding of the clinical relevance of the microenvironmental immunological milieu might provide an important clue for the design of novel strategies in cancer immunotherapy.     

榄香烯治疗非小细胞肺癌的作用机制研究进展

榄香烯注射液是从天然中草药姜科植物温郁金中提取获得的萜烯类化合物,其主要生物学活性为降低肿瘤细胞有丝分裂能力,诱导肿瘤细胞凋亡,抑制肿瘤细胞的生长,从而改善NSCLC患者的临床症状,增强患者免疫力.本文主要从杀灭癌细胞、诱导癌细胞凋亡、抑制癌细胞血管形成、增强患者免疫力等几方面综述榄香烯注射液对非小细胞肺癌的作用机制.     

XPA 及XPG 基因多态性与晚期非小细胞肺癌铂类药物化疗疗效及 预后的关系

目的:研究DNA修复基因XPAA23G及XPGC46T位点基因多态性与晚期非小细胞肺癌铂类化疗疗效及预后的关系。方法:经病理学确诊的晚期非小细胞肺癌患者89例,化疗前提取其外周血DNA,用DNA测序技术检测XPA、XPG基因型,所有患者均接受2-4个周期铂类药物为基础的化疗。结果:1)89例患者中,携带XPA23A/A及A/G+G/G基因型的化疗有效率分别为47.5%和24.5%,差异有统计学意义(x2=5.137,P=0.023);携带XPG46C/C及C/T+T/T基因型的患者治疗有效率分别为47.6%、23.4%,二者间也有统计学差异(x2=5.729,P=0.017),联合分析显示A/A及C/C型化疗有效率最高,达63.0%,而A/A及C/T+T/T型最低,仅15.4%,四组间有显著统计学差异(x2=14.080,P=0.003)。2)89例患者中位TTP为7个月,XPA23A/A基因型中位TTP为11个月,A/G+G/G基因型为6个月,两者比较差异有显著性(x2=44.640,P<0.01);XPG46C/C基因型中位TTP为10个月,C/T+T/T基因型为6个月,两者也有统计学差异(x2=32.236,P<0.01)。联合分析显示,XPAA/A+XPGC/C型中位TTP最长,达到11个月,而A/G+G/G及C/T+T/T基因型最短,仅有4个月,四组间差异有显著统计学意义(x2=59.295,P<0.01)。结论:XPAA23G及XPGC46T单核苷酸多态性可单独及联合用于预测晚期NSCLC病人对铂类药物的化疗疗效及TTP,初步提示可以根据患者基因型来指导个体化治疗。     

XPA及XPG基因多态性与晚期非小细胞肺癌铂类药物化疗疗效及预后的关系

目的：研究DNA修复基因XPAA23G及XPGC46T位点基因多态性与晚期非小细胞肺癌铂类化疗疗效及预后的关系。方法：经病理学确诊的晚期非小细胞肺癌患者89例,化疗前提取其外周血DNA,用DNA测序技术检测XPA、XPG基因型,所有患者均接受2-4个周期铂类药物为基础的化疗。结果：1）89例患者中,携带XPA23A/A及A/G＋G/G基因型的化疗有效率分别为47.5%和24.5%,差异有统计学意义（x2=5.137,P=0.023）;携带XPG46C/C及C/T＋T/T基因型的患者治疗有效率分别为47.6%、23.4%,二者间也有统计学差异（x2=5.729,P=0.017）,联合分析显示A/A及C/C型化疗有效率最高,达63.0%,而A/A及C/T＋T/T型最低,仅15.4%,四组间有显著统计学差异（x2=14.080,P=0.003）。2）89例患者中位TTP为7个月,XPA23A/A基因型中位TTP为11个月,A/G＋G/G基因型为6个月,两者比较差异有显著性（x2=44.640,P〈0.01）;XPG46C/C基因型中位TTP为10个月,C/T＋T/T基因型为6个月,两者也有统计学差异（x2=32.236,P〈0.01）。联合分析显示,XPAA/A＋XPGC/C型中位TTP最长,达到11个月,而A/G＋G/G及C/T＋T/T基因型最短,仅有4个月,四组间差异有显著统计学意义（x2=59.295,P〈0.01）。结论：XPAA23G及XPGC46T单核苷酸多态性可单独及联合用于预测晚期NSCLC病人对铂类药物的化疗疗效及TTP,初步提示可以根据患者基因型来指导个体化治疗。