Emerging therapeutic agents for lung cancer

Lung cancer continues to be the most common cause of cancer-related mortality worldwide. Recent advances in molecular diagnostics and immunotherapeutics have propelled the rapid development of novel treatment agents across all cancer subtypes, including lung cancer. Additionally, more pharmaceutical therapies for lung cancer have been approved by the US Food and Drug Administration in the last 5 years than in previous two decades. These drugs have ushered in a new era of lung cancer managements that have promising efficacy and safety and also provide treatment opportunities to patients who otherwise would have no conventional chemotherapy available. In this review, we summarize recent advances in lung cancer therapeutics with a specific focus on first in-human or early-phase I/II clinical trials. These drugs either offer better alternatives to drugs in their class or are a completely new class of drugs with novel mechanisms of action. We have divided our discussion into targeted agents, immunotherapies, and antibody drug conjugates for small cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC). We briefly review the emerging agents and ongoing clinical studies. We have attempted to provide the most current review on emerging therapeutic agents on horizon for lung cancer.     

EGFR基因21外显子L858R突变肺腺癌患者化疗和靶向治疗疗效的对比研究

目的:研究化疗和靶向治疗对EGFR基因21外显子L858R突变肺腺癌患者的临床疗效和患者生存率的影响。方法:选择2012年1月~2016年1月在重庆市肿瘤医院治疗的95例EGFR基因21外显子L858R突变的肺腺癌患者,按患者治疗方式不同分为化疗组(n=54)和靶向组(n=41)。化疗组患者采用一线化疗药物进行治疗,靶向组患者采用EGFR基因靶向制剂进行治疗。在完成一个周期治疗后,比较两组患者的近期疗效及治疗过程中不良反应的发生情况。对患者进行为期1年的随访,比较其生存情况。结果:(1)化疗组患者治疗后临床总有效率为92.59%(50/54),靶向组总有效率为73.17%(30/41),化疗组显著高于靶向治疗组(P=0.010)。(2)化疗组不良反应发生率为25.93%(14/54),靶向治疗组则为19.51%(8/41),组间比较差异无统计学意义(P=0.463)。(3)在随访过程中,化疗组患者有18例死亡,36例存活,患者生存率为例66.67%;靶向组患者有24例死亡,17例存活,患者生存率为41.46%,化疗组生存率显著高于靶向治疗组(P=0.014)。结论:对于EGFR基因21外显子L858R突变肺腺癌患者而言,采用化疗治疗的疗效明显优于靶向治疗,且二者安全性相当,化疗治疗的患者预后较靶向治疗者更好。     

以EGFR为靶点的肿瘤分子靶向药物研究进展

随着分子生物学研究的进展,分子靶向治疗已成为除手术、放疗、化疗之外的第4种治疗方法,越来越多的用于临床治疗恶性肿瘤。分子靶向药物进入体内能够特异地选择致癌位点,杀伤肿瘤细胞,而不会波及周围正常的组织细胞,因此分子靶向治疗又被称为"生物导弹"。与传统化疗药物相比,分子靶向药物具有特异性强、疗效明显、副作用少等优点。按照分子靶向药物的性质主要归为两大类:一类是单克隆抗体,如西妥昔单抗等;另一类是单靶点或多靶点的小分子抑制剂,如吉非替尼等。表皮生长因子受体(EGFR)对肿瘤的生长、发展以及肿瘤干细胞的维持都有着非常重要的作用,并且在多种实体瘤中存在过表达或异常表达,因此在肿瘤治疗中,EGFR成为一个非常重要的用药靶点。现主要对目前国内已上市的针对EGFR的分子靶向药物最新的临床研究进展作一简要综述。     

Visualizing lung function with positron emission tomography.

Positron emission tomography (PET) provides three-dimensional images of the distributions of radionuclides that have been inhaled or injected into the lungs. By using radionuclides with short half-lives, the radiation exposure of the subject can be kept small. By following the evolution of the distributions of radionuclides in gases or compounds that participate in lung function, information about such diverse lung functions as regional ventilation, perfusion, shunt, gas fraction, capillary permeability, inflammation, and gene expression can be inferred. Thus PET has the potential to provide information about the links between cellular function and whole lung function in vivo. In this paper, recent advancements in PET methodology and techniques and information about lung function that have been obtained with these techniques are reviewed.     

Dynamic BH3 profiling identifies active BH3 mimetic combinations in non-small cell lung cancer

Conventional chemotherapy is still of great utility in oncology and rationally constructing combinations with it remains a top priority. Drug-induced mitochondrial apoptotic priming, measured by dynamic BH3 profiling (DBP), has been shown in multiple cancers to identify drugs that promote apoptosis in vivo. We therefore hypothesized that we could use DBP to identify drugs that would render cancers more sensitive to conventional chemotherapy. We found that targeted agents that increased priming of non-small cell lung cancer (NSCLC) tumor cells resulted in increased sensitivity to chemotherapy in vitro. To assess whether targeted agents that increase priming might enhance the efficacy of cytotoxic agents in vivo as well, we carried out an efficacy study in a PC9 xenograft mouse model. The BH3 mimetic navitoclax, which antagonizes BCL-xL, BCL-w, and BCL-2, consistently primed NSCLC tumors in vitro and in vivo. The BH3 mimetic venetoclax, which electively antagonizes BCL-2, did not. Combining navitoclax with etoposide significantly reduced tumor burden compared to either single agent, while adding venetoclax to etoposide had no effect on tumor burden. Next, we assessed priming of primary patient NSCLC tumor cells on drugs from a clinically relevant oncology combination screen (CROCS). Results confirmed for the first time the utility of BCL-xL inhibition by navitoclax in priming primary NSCLC tumor cells and identified combinations that primed further. This is a demonstration of the principle that DBP can be used as a functional precision medicine tool to rationally construct combination drug regimens that include BH3 mimetics in solid tumors like NSCLC.Subject terms: Non-small-cell lung cancer, Apoptosis, Predictive markers     

非小细胞肺癌的免疫治疗进展

肺癌是最致命的恶性肿瘤之一,也是男性肿瘤患者致死率最高的,5年生存率低于18%。尽管非小细胞肺癌(non-small cell lung cancer,NSCLC)在手术治疗、化疗、放疗以及靶向治疗方面均取得了一定的成果,但晚期NSCLC的预后依然很差。免疫治疗为NSCLC患者提供了一个新的治疗方向。免疫治疗目前主要研究方向在免疫检查点抑制剂(Ipilimumab、Nivolumab、MK-3475)和肿瘤疫苗(MAGE-A3,L-BLP25,TG4010,Belagenpumatucel-L)等。免疫治疗具有针对性强、副作用少、效率高的特点,并在Ⅱ、Ⅲ期临床试验中取得了较好的疗效,成为在手术、化疗、放疗以及靶向治疗后一种新的重要治疗手段。本文就当前非小细胞肺癌免疫治疗原理、临床试验及待解决问题作一综述。     

支气管动脉灌注化疗与栓塞治疗中晚期肺癌的疗效观察

目的：对比分析支气管动脉灌注化疗与支气管动脉灌注化疗十栓塞术治疗中晚期肺癌的临床疗效。方法：将我院2011年1月-2013年1月期间收治的76例中晚期肺癌患者随机分为两组,即观察组38例,对照组38例。观察组患者行支气管动脉灌注化疗联合栓塞术治疗,对照组患者行单纯支气管动脉灌注化疗治疗。分别对两组患者治疗后的临床治疗效果进行评价,同时观察两组患者治疗后的不良反应及并发症的发生情况。结果：观察组患者临床治疗的总有效率为84．21％,对照组为64．78％．两组比较,差异具有统计学意义（P〈0．05）。两组患者治疗后,观察组患者总不良反应率为23．67％,对照组为21．04％,两组比较．差异无统计学意义（P〉0．05）。且经对症处理后,均得到有效改善。结论：支气管动脉灌注化疗联合栓塞术治疗中晚期肺癌的,临床疗效明显优于单纯支气管动脉灌注化疗,且无明显不良反应及并发症的发生,安全性好,值得临床推广与应用。     

晚期非小细胞肺癌p53 和ERCC1 表达状态与顺铂为主的 联合方案化疗的近期有效率的相关性研究*

目的:研究晚期非小细胞肺癌不同的p53和ERCC1表达状态与基于顺铂为主的姑息化疗近期有效率的相关性。方法:对经顺铂联合多西他赛或顺铂联合吉西他滨治疗的48例晚期非小细胞肺癌患者进行回顾性分析,利用既往免疫组化资料,观察基于顺铂为主的方案近期有效率(RR)的影响因素及化疗不良反应。结果:全组48例患者均完成至少两周期化疗,并行疗效评价。该组患者化疗的近期有效率为28例(58.3%),RR与不同的转移病灶部位(P=0.042)及病灶数目(P=0.034)有显著差异。该类方案的近期有效率与ERCC1状态(P=0.012)密切相关,而与p53表达状态(P=0.401)无关。毒性反应主要是骨髓抑制、脱发及消化道反应等。结论:晚期非小细胞肺癌ERCC1阴性患者较ERCC1阳性患者运用顺铂为主的联合方案化疗的近期有效率较高。ERCC1可能是顺铂疗效预测的敏感因子。p53的表达状态可能不是该类方案的疗效预测因子。     

The Efficacy of Bevacizumab Compared with Other Targeted Drugs for Patients with Advanced NSCLC: A Meta-Analysis from 30 Randomized Controlled Clinical Trials

Background

The extent of the benefit of bevacizumab combined with chemotherapy in the treatment of advanced non-small-cell lung cancer (NSCLC) is still unclear. We performed this meta-analysis to compare the efficacy of bevacizumab with other commonly used targeted drugs for different patients with advanced NSCLC.

Methods

We searched PubMed, Cochrane Library, EMBASE and abstracts from the proceedings of the American Society of Clinical Oncology (ASCO), and identified 30 randomized controlled clinical trials published within 1999 to 2011 for meta-analysis.

Results

The outcomes of treatment efficacy included response rate, PFS and OS. Comparing bevacizumab (15 mg/kg) with chemotherapy to standard chemotherapy alone, for chemotherapy-naïve patients, the pooled OR of response rate was 2.741(95%CI: 2.046, 3.672), the pooled HR for disease progression was 0.645 (95%CI: 0.561, 0.743), and the pooled HR for death was 0.790 (95%CI: 0.674, 0.926), respectively. In addition, the adjusted HR for previously-treated patients was 0.680 (95%CI: 0.492, 0.942) comparing bevacizumab combined with chemotherapy to standard chemotherapy alone.

Conclusions

Bevacizumab accompanied by chemotherapy was found to significantly improve patients'' response rate, progression free survival (PFS), and overall survival (OS) among chemotherapy-naïve patients compared to other targeted drugs in the treatment of non-small cell lung carcinoma (NSCLC).     

Advances in magnetic resonance imaging of lung physiology.

This review presents an overview of some recent magnetic resonance imaging (MRI) techniques for measuring aspects of local physiology in the lung. MRI is noninvasive, relatively high resolution, and does not expose subjects to ionizing radiation. Conventional MRI of the lung suffers from low signal intensity caused by the low proton density and the large degree of microscopic field inhomogeneity that degrades the magnetic resonance signal and interferes with image acquisition. However, in recent years, there have been rapid advances in both hardware and software design, allowing these difficulties to be minimized. This review focuses on some newer techniques that measure regional perfusion, ventilation, gas diffusion, ventilation-to-perfusion ratio, partial pressure of oxygen, and lung water. These techniques include contrast-enhanced and arterial spin-labeling techniques for measuring perfusion, hyperpolarized gas techniques for measuring regional ventilation, and apparent diffusion coefficient and multiecho and gradient echo techniques for measuring proton density and lung water. Some of the major advantages and disadvantages of each technique are discussed. In addition, some of the physiological issues associated with making measurements are discussed, along with strategies for understanding large and complex data sets.     

Tumor-targeting amino acid auxotrophic <Emphasis Type="Italic">Salmonella typhimurium</Emphasis>

We have developed an effective bacterial cancer therapy strategy by targeting viable tumor tissue using Salmonella typhimurium auxotrophs that we have generated which grow in viable as well as necrotic areas of tumors. However, the auxotrophy severely restricts growth of these bacteria in normal tissue. The S. typhimurium A1-R mutant, which is auxotrophic for leu-arg and has high anti-tumor virulence, was developed in our laboratory. In vitro, A1-R infects tumor cells and causes nuclear destruction. A1-R was initially used to treat metastatic human prostate and breast tumors that had been orthotopically implanted in nude mice. Forty percent of treated mice were cured completely and survived as long as non-tumor-bearing mice. A1-R administered i.v. to nude mice with primary osteosarcoma and lung metastasis was highly effective, especially against metastasis. A1-R was also targeted to both axillary lymph and popliteal lymph node metastasis of human pancreatic cancer and fibrosarcoma, respectively, as well as lung metastasis of the fibrosarcoma in nude mice. The bacteria were delivered via a lymphatic channel to target the lymph node metastases and systemically via the tail vein to target the lung metastasis. The metastases were cured without the need of chemotherapy or any other treatment. A1-R was administered intratumorally to nude mice with an orthotopically transplanted human pancreatic tumor. The primary pancreatic cancer regressed without additional chemotherapy or any other treatment. A1-R was also effective against pancreatic cancer liver metastasis when administered intrasplenically to nude mice. The approach described here, where bacterial monotherapy effectively treats primary and metastatic tumors, is a significant improvement over previous bacterial tumor-therapy strategies that require combination with toxic chemotherapy. Three promoter clones engineered in S. enterica typhimurium were identified to have enhanced expression in bacteria growing in tumors relative to those growing in the spleen. The expression of therapeutics in Salmonella under the regulation of one or more promoters that are activated preferentially in tumors has the potential to improve the efficacy of Salmonella tumor therapy. Exploitation of the tumor-killing capability of Salmonella has great promise for a new paradigm of cancer therapy.     

Prise en charge du cancer du sein,avancées et perspectives

Breast cancer treatment has developed rapidly for the last 15 years, promoted by a better understanding of tumour growth biology. Targeted therapies have been rapidly expending: immunotherapy, targeted chemotherapy, endocrine therapy efficacy enhanced by mTOR inhibitors. Changes of molecular profiling tumours during the illness need to perform regularly biopsies and to adapt drugs. This article will focus on a high-level overview of main advances across systemic treatment.     

EGFR tyrosine kinase inhibitors activate autophagy as a cytoprotective response in human lung cancer cells

Epidermal growth factor receptor tyrosine kinase inhibitors gefitinib and erlotinib have been widely used in patients with non-small-cell lung cancer. Unfortunately, the efficacy of EGFR-TKIs is limited because of natural and acquired resistance. As a novel cytoprotective mechanism for tumor cell to survive under unfavorable conditions, autophagy has been proposed to play a role in drug resistance of tumor cells. Whether autophagy can be activated by gefitinib or erlotinib and thereby impair the sensitivity of targeted therapy to lung cancer cells remains unknown. Here, we first report that gefitinib or erlotinib can induce a high level of autophagy, which was accompanied by the inhibition of the PI3K/Akt/mTOR signaling pathway. Moreover, cytotoxicity induced by gefitinib or erlotinib was greatly enhanced after autophagy inhibition by the pharmacological inhibitor chloroquine (CQ) and siRNAs targeting ATG5 and ATG7, the most important components for the formation of autophagosome. Interestingly, EGFR-TKIs can still induce cell autophagy even after EGFR expression was reduced by EGFR specific siRNAs. In conclusion, we found that autophagy can be activated by EGFR-TKIs in lung cancer cells and inhibition of autophagy augmented the growth inhibitory effect of EGFR-TKIs. Autophagy inhibition thus represents a promising approach to improve the efficacy of EGFR-TKIs in the treatment of patients with advanced non-small-cell lung cancer.     

氯喹抑制铁蛋白自噬并增强肺癌细胞对化疗药物敏感性的研究

目的肺癌的发病率和致死率高居世界恶性肿瘤首位。尽管肺癌的诊断与治疗治疗已取得进展,但其发病率和致死率仍呈逐年上升的趋势,因此急需寻找有效的干预靶标和治疗手段。方法本文验证了通过自噬抑制剂干预铁蛋白自噬、增加肺癌细胞对化疗药物敏感性的多药联用策略。通过免疫印迹分析及免疫荧光测定了细胞中铁蛋白的自噬性降解(铁蛋白自噬),通过分析细胞数量及细胞周期测定了细胞增殖,通过分析细胞耗氧速率评估了细胞线粒体氧化磷酸化水平。结果铁螯合剂去铁胺可诱导肿瘤细胞发生铁蛋白自噬;氯喹等自噬抑制剂可有效抑制去铁胺诱导的铁蛋白降解,显著抑制肿瘤细胞线粒体氧化磷酸化,并引发细胞周期阻滞、抑制细胞增殖;去铁胺、氯喹与一线化疗药物顺铂或依托泊苷的联合给药可显著增强化疗药物对肺癌细胞的毒性。结论通过自噬抑制剂和铁螯合剂干预细胞铁代谢有望成为提升肺癌化疗治疗效果的潜在新策略。     

Measurement of subclinical atherosclerosis: beyond risk factor assessment

PURPOSE OF REVIEW: Assessment of subclinical atherosclerosis using the current available noninvasive imaging modalities holds promise for individual cardiovascular risk management and monitoring efficacy of therapeutic interventions (i.e. surrogate end-points). The present review addresses benefits and limitations of flow-mediated dilatation, intima-media thickness, electron-beam computed tomography and magnetic resonance coronary angiography. RECENT FINDINGS: Both carotid intima-media thickness and peripheral flow-mediated dilatation correlate inversely with cardiovascular risk factors and coronary artery disease. They have been shown to carry predictive value for future cardiovascular events, but clinical application of both intima-media thickness and flow-mediated dilatation demands further methodological maturation of these techniques. Intima thickening has been successfully targeted in numerous intervention trials, but determination of an explicit threshold value beyond which cardiovascular risk significantly increases will facilitate its utility as a routine clinical tool. Electron-beam computed tomography can accurately detect and quantify coronary artery calcification (an established marker of the total coronary plaque burden). However, lack of evidence of its additional predictive power for future coronary events warrants for further research. Finally, magnetic resonance coronary angiography appears to be a promising technique, integrating both functional and anatomical aspects of coronary artery disease. Properly designed studies are needed to determine its value in clinical practice. SUMMARY: Various noninvasive imaging techniques have recently emerged that may find applications in clinical research. However, before widespread clinical utilization, further technical refinement of all of the cited imaging modalities is mandatory. It will be a challenge over the coming few years to clarify whether improvements in surrogate end-points can directly be translated into improved outcomes.     

Gene therapy for lung cancer

Lung cancer patients suffer a 15% overall survival despite advances in chemotherapy, radiation therapy, and surgery. This unacceptably low survival rate is due to the usual finding of advanced disease at diagnosis. However, multimodality strategies using conventional therapies only minimally improve survival rates even in early stages of lung cancer. Attempts to improve survival in advanced disease using various combinations of platinum-based chemotherapy have demonstrated that no regimen is superior, suggesting a therapeutic plateau and the need for novel, more specific, and less toxic therapeutic strategies. Over the past three decades, the genetic etiology of cancer has been gradually delineated, albeit not yet completely. Understanding the molecular events that occur during the multistep process of bronchogenic carcinogenesis may make these tasks more surmountable. During these same three decades, techniques have been developed which allow transfer of functional genes into mammalian cells. For example, blockade of activated tumor-promoting oncogenes or replacement of inactivated tumor-suppressing or apoptosis-promoting genes can be achieved by gene therapy. This article will discuss the therapeutic implications of these molecular changes associated with bronchogenic carcinomas and will then review the status of gene therapies for treatment of lung cancer.     

Hemorrhage associated with hepatic artery pseudoaneurysms after regional chemotherapy with floxuridine: case report

Pseudoaneurysms of the hepatic artery are a rare complication in patients with primary or secondary liver tumors treated with intra-arterial chemotherapy. We present two patients who developed this complication after placement of a catheter system into the gastroduodenal artery and initiation of regional chemotherapy with floxuridine. Diagnosis was made after symptomatic bleeding occurred, necessitating emergency angiography with coil embolization. Pseudoaneurysms usually occur after mechanical damage of the vessel wall, but the chemical toxicity of floxuridine may add to the development of vascular impairment.     

Nanoparticle-mediated targeted drug delivery for breast cancer treatment

Breast cancer (BC) is the most common malignancy in women worldwide, and one of the deadliest after lung cancer. Currently, standard methods for cancer therapy including BC are surgery followed by chemotherapy or radiotherapy. However, both chemotherapy and radiotherapy often fail to treat BC due to the side effects that these therapies incur in normal tissues and organs. In recent years, various nanoparticles (NPs) have been discovered and synthesized to be able to selectively target tumor cells without causing any harm to the healthy cells or organs. Therefore, NPs-mediated targeted drug delivery systems (DDS) have become a promising technique to treat BC. In addition to their selectivity to target tumor cells and reduce side effects, NPs have other unique properties which make them desirable for cancer treatment such as low toxicity, good compatibility, ease of preparation, high photoluminescence (PL) for bioimaging in vivo, and high loadability of drugs due to their tunable surface functionalities. In this study, we summarize with a critical analysis of the most recent therapeutic studies involving various NPs-mediated DDS as alternatives for the traditional treatment approaches for BC. It will shed light on the significance of NPs-mediated DDS and serve as a guide to seeking for the ideal methodology for future targeted drug delivery for an efficient BC treatment.     

General treatment for metastatic colorectal cancer: From KEYNOTE 177 study

In the palliative treatment of metastatic colorectal cancer (mCRC), doublet chemotherapy (FOLFOX or FOLFIRI) or triplet chemotherapy (FOLFOXIRI) combined with targeted drugs (cetuximab or bevacizumab) is the main regimen. Recently, microsatellite instability-high (MSI-H) or DNA mismatch repair deficient (dMMR) was discovered as a biomarker to distinguish immunotherapy-benefited populations. In this context, recently published randomized phase III clinical trials tested the efficacy and safety of immunotherapy and traditional chemotherapy with or without targeted drugs as first-line treatment for patients with MSI-H/dMMR mCRC.Here, we briefly analyze this article and further discuss immune monotherapy or double immunotherapy for patients with MSI-H/dMMR mCRC, the immunotherapy for patients with BRAF V600E mutant mCRC, and the immunotherapy for patients with microsatellite stable mCRC.