Targeting tyrosine kinases in cancer

Because of knowledge gained in the field of cancer biology, clinicians are currently witnessing an explosion of molecular tests as companion diagnostics to targeted therapies against growth factor receptors and their signaling pathways. Such tests are being applied increasingly to cytology specimens as essential components of genomic medicine, because less invasive diagnostic procedures are becoming the norm. The objective of this review was to present an overview of the current and future role of cytopathology in molecular diagnostics, including the adequacy of cytology specimens for such studies. The authors also discuss the critical methodologic aspects of the molecular assays used for the selection of tyrosine kinase treatment for oncology patients. Cancer (Cancer Cytopathol) 2013. © 2012 American Cancer Society.     

Targeting receptor tyrosine kinases and their signal transduction routes in head and neck cancer.

Squamous cell carcinoma of the head and neck (SCCHN) is the sixth most common cancer in the world. At present several therapeutic approaches, including surgical removal, chemotherapy and radiotherapy, are used. Yet a significant number of patients relapse, often with metastases. In an attempt to improve treatment of SCCHN new targeted therapies are emerging. Among them special interest has been devoted to agents that act on the epidermal growth factor receptor (EGFR) and other receptor tyrosine kinases, or the signal transduction routes used by these receptors to induce tumour cell proliferation. Such treatments include monoclonal antibodies and small molecule inhibitors of either the intracellular tyrosine kinase activity of these receptors or relevant signalling intermediates. Here we review the biological bases of these new targeted treatments, with special emphasis on the clinical results that point to an implementation of these drugs into the therapeutic armamentarium against SCCHN.     

Targeting protein geranylgeranylation slows tumor development in a murine model of prostate cancer metastasis

The isoprenoid biosynthetic pathway (IBP) plays a critical role in providing substrates and enzymes necessary for the post-translational modification and thus activation of a number of proteins involved in prostate cancer metastasis. Previous work by our lab found novel compound disodium [(6Z,11E,15E)-9-[bis(sodiooxy)phosphoryl]?17-hydroxy-2,6,12,16-tetramethyheptadeca-2,6,11,15-tetraen-9-yl]phosphonate (GGOHBP), which inhibits the IBP enzyme geranylgeranyl diphosphate synthase (GGDPS), reduced protein geranylgeranylation without altering protein farnesylation. This activity significantly reduced adrenal gland tumor burden in a murine model of human prostate cancer metastasis which relied on treatment of established disease. The present study determined the ability of GGDPS inhibition to slow the development of prostate cancer metastasis in a preventative murine model. Using tail vein injection of human derived PC-3 prostate cancer cells 4 d after initiating daily GGOHBP or vehicle treatments, we found GGOHBP significantly reduced whole body tumor burden, significantly slowed the development of tumors, and prolonged overall survival as compared to vehicle treated animals. The observed reduction in soft tissue tumor burden corresponded to a biochemical reduction in Rap1A geranylgeranylation, which for prostate cancer is important in its own merit and which serves as a surrogate marker for Rho family, i.e. Rac, protein modification. This effect was present in all treated mice pointing to strong target engagement, which was not observed in non-tumor burdened tissues or control mice. Our findings reiterate a role for protein geranylgeranylation in the development of prostate cancer metastasis in vivo.     

靶向肿瘤胆固醇代谢：机遇与挑战

胆固醇是细胞膜的重要组成成分,异常的胆固醇代谢不仅和心血管疾病密切相关,也和肿瘤的发生、发展密不可分。肿瘤细胞在侵袭和转移的过程中,需要大量的胆固醇来满足自身快速生长的物质需求。胆固醇不能在体内代谢为二氧化碳和水,参与供能。大量累积的胆固醇会代谢为不同生物功能的次级产物,参与微环境里的代谢调控和免疫调控,进一步促进肿瘤的发生、发展。在肿瘤发生、发展过程中,肿瘤细胞内或者细胞外的改变会触发胆固醇的代谢改变,从而促进肿瘤的生长。另外,微环境里的免疫细胞,也需要胆固醇来维持自身正常功能的需要,单纯的降低血清胆固醇可能会损害免疫功能,促进肿瘤生长。肿瘤细胞和免疫细胞对微环境中胆固醇的抢夺以及胆固醇的代谢产物相互之间的影响,构成了微环境中胆固醇调控的复杂体系。因此,阐明肿瘤细胞和免疫细胞胆固醇代谢的特点,是靶向胆固醇代谢的抗肿瘤策略的关键,而基于靶向胆固醇代谢的联合治疗有望提高某些特定胆固醇代谢特征的肿瘤患者疗效。     

Contract research organizations in oncology clinical research: Challenges and opportunities

Contract research organizations (CROs) represent a multibillion dollar industry that is firmly embedded in the contemporary clinical trial process. Over the past 30 years, and especially within the last decade, the reach of CROs has extended to service all phases of drug trials in an increasingly global research environment. The presence of CROs is particularly noticeable in medical oncology because of the large number of investigational compounds developed to treat cancer that are currently undergoing testing in human subjects. Although limited data are available with which to objectively define the effects that CROs have had on the clinical trial process, with the expansion of these organizations, several reports have called into question whether ethical and professional standards in research conduct are at times secondary to economic considerations. CROs can add considerable value to the clinical trial process, but difficulty communicating with CRO representatives and time spent answering trivial data queries generated by CROs are current obstacles for study site personnel interacting with CROs. Further study of the effect of the CRO industry on the clinical trial process is needed to ensure efficient data collection and patient safety while collaboratively developing novel therapies in an expedited fashion. Cancer 2016;122:1476–82 . © 2016 American Cancer Society.     

Targeting claudins in cancer: diagnosis,prognosis and therapy

Increasing evidence has linked claudins to signal transduction and tumorigenesis. The expression of claudins is frequently dysregulated in the context of neoplastic transformation, suggesting their promise as biomarkers for diagnosis and prognosis or targets for treatment. Claudin binders (Clostridium perfringens enterotoxin and monoclonal antibody) have been tested in preclinical experiments, and some of them have progressed into clinical trials involving patients with certain cancers. However, the clinical development of many of these agents has not advanced to clinical applications. Herein, I review the current status of preclinical and clinical investigations of agents targeting claudins for diagnosis, prognosis and therapy. I also discuss the potential of combining claudin binders with other currently approved therapeutic agents.     

难治性甲状腺癌靶向治疗Meta分析

目的 目前对于进展期甲状腺癌分子靶向治疗的研究多为单臂实验,RCT研究较少.本研究应用Meta分析方法,评价分子靶向治疗在难治性甲状腺癌中的疗效和安全性,以期为其应用提供理论基础.方法 检索纳入1989-01-2015-01 Medline、Web of science、Cochrane Central、EBSCO、Embase等英文数据库及中国学术期刊全文数据库、万方、维普等中文数据库中的文献.按照纳入与排除标准进行文献筛选和质量评价后,利用Cochrane中心提供的RevMan5.0软件对数据进行分析.主要评价指标是患者的无进展生存率及药物的不良反应.结果 共纳入4项随机对照试验研究,得到药物组总体样本730例,对照组(安慰剂组)总体样本493例.相比对照组,药物组6、12和18个月的无进展生存率均显著提高(6个月:RR=2.57,95％CI为1.97～3.35;12个月:RR=2.01,95％CI为1.53～2.65;18个月:RR=2.10,95％CI为1.54～2.87).药物组不良反应发生率高于对照组(RR=4.20,95％CI为2.82～6.24).主要是腹泻、疲劳、高血压、手足综合征和QT间期延长.结论 靶向药物可显著延长难治性甲状腺癌患者的无进展生存期.虽然其不良反应发生率显著高于对照组,但患者仍可耐受.靶向治疗为难治性甲状腺癌患者带来新的希望.     

Drug development in advanced colorectal cancer: Challenges and opportunities

Despite recent advances in treatment options, advanced colorectal cancer (ACC) remains a leading cause of cancer death worldwide, and new therapies are needed to improve the grim prognosis of this disease. Drug development in ACC faces the challenges of a constrained pipeline, a paucity of patients enrolled in clinical trials, and an outdated “one drug fits all” model of clinical research. This article discusses potential innovations in clinical trial design—including enrichment strategies, novel patient populations, and the use of randomization in the phase 2 setting—to optimize the testing of new therapies. It concludes with a selection of promising agents and pathways under investigation in ACC.     

Current epidemiology of pancreatic cancer: Challenges and opportunities

Pancreatic cancer(PC) is an increasingly common disease worldwide. Having a better understanding of worldwide and regional epidemiologic features and risk factors of PC is essential to identify new approaches for prevention,early diagnosis, surveillance, and treatment. In this article, we review the epidemiologic features and risk factors for PC and discuss opportunities and challenges of PC future treatment.     

Molecular targets in melanoma: strategies and challenges for diagnosis and therapy

In coming years, we expect rapid advances in cutaneous melanoma diagnosis and therapy, because of the incorporation of new technologies into experimental and clinical research. Major discoveries in melanoma are often made by investigators outside the field, and the melanoma research community will need to develop a better means of incorporating these advances into their work, to capitalize on the promise they hold for patients. A far greater level of cooperation between labs and clinics will be to bring new technology-based discoveries from bench-to-bedside and back. Metastatic melanoma should become a treatable disease in the next few years, because specific inhibitors are expected for most major targets. However, major challenges lie ahead in securing funding, building infrastructure and gaining expertise in new technologies. To meet these challenges, multidisciplinary collaborations will be required all the more.     

Role of STK11 in ALK-positive non-small cell lung cancer

Anaplastic lymphoma kinase (ALK) inhibitors have been shown to be effective in treating patients with ALK-positive non-small cell lung cancer (NSCLC), and crizotinib, ceritinib and alectinib have been approved as clinical first-line therapeutic agents. The availability of these inhibitors has also largely changed the treatment strategy for advanced ALK-positive NSCLC. However, patients still inevitably develop resistance to ALK inhibitors, leading to tumor recurrence or metastasis. The most critical issues that need to be addressed in the current treatment of ALK-positive NSCLC include the high cost of targeted inhibitors and the potential for increased toxicity and resistance to combination therapy. Recently, it has been suggested that the serine/threonine kinase 11 (STK11) mutation may serve as one of the biomarkers for immunotherapy in NSCLC. Therefore, the main purpose of this review was to summarize the role of STK11 in ALK-positive NSCLC. The present review also summarizes the treatment and drug resistance studies in ALK-positive NSCLC and the current status of STK11 research in NSCLC.     

Targeting molecular addictions in cancer

Cancer cells depend on a finite number of critical signals for their survival. Oncogene addiction, that is, the acquired dependence of a cancer cell on the activity of a single oncogenic gene product, has been the basis for the targeted therapy paradigm, and operationally defines such signals. Additionally, cancer cells have altered metabolic requirements that create addictions to specific nutrients such as glucose and glutamine. In this review, I will discuss the therapeutic opportunities that these two types of molecular addictions offer, focusing on lessons learned from targeting members of the epidermal growth factor receptor family of kinases, and components of MAPK pathway. I will also discuss the challenges in simultaneously harnessing two types of molecular addictions for therapeutic benefit, and the importance of understanding not only the effects of oncogenic signal transduction on metabolism, but also the impact of metabolic states on signal transduction.     

Towards third generation matrix metalloproteinase inhibitors for cancer therapy

The failure of matrix metalloproteinase (MMP) inhibitor drug clinical trials in cancer was partly due to the inadvertent inhibition of MMP antitargets that counterbalanced the benefits of MMP target inhibition. We explore how MMP inhibitor drugs might be developed to achieve potent selectivity for validated MMP targets yet therapeutically spare MMP antitargets that are critical in host protection.     

乳腺癌骨转移差异基因的生物信息学分析

目的:在生物信息学数据库中挖掘乳腺癌骨转移的差异表达基因(differentially expressed genes,DEGs),探讨DEGs的细胞定位、分子功能及其潜在的分子机制,寻找乳腺癌骨转移的潜在治疗靶点和预后预测基因.方法:通过在基因表达数据库(GEO)中筛选乳腺癌骨转移相关芯片数据,使用RStudio对芯...     

Targeting p73 in cancer

p73 is a member of the p53 family of tumor suppressors. Transactivating isoforms of p73 (TAp73) have p53-like, anti-proliferative and pro-apoptotic activities that are crucial for an efficient chemotherapy response. In line with this, genetic studies in mice have confirmed that TAp73 acts as a tumor suppressor. However, in contrast to p53, which is commonly inactivated in human cancer by point mutations, the TP73 gene is almost never mutated. Instead, the tumor suppressor activity of TAp73 is inhibited through a variety of mechanisms including epigenetic silencing and complex formation with inhibitory proteins. All these mechanisms have in common that they are in principle reversible and therefore amenable to therapeutic intervention. Here, we will review how tumor cells control the tumor suppressor activity of TAp73 and discuss possible strategies targeting p73 for reactivation.     

Molecularly targeted therapy: toxicity and quality of life considerations in advanced colorectal cancer

Colorectal cancer (CRC) is the third most common malignancy and cause of death from cancer among adults worldwide. In recent years, the use of 5-fluorouracil-based regimens in combination with molecularly targeted agents has greatly expanded treatment options for patients with metastatic disease. With a more capillary use of this new class of agents comes the recognition of diverse adverse events related to disturbance of critical biological pathways involved in physiological functions. Proactive management and prevention of adverse events, with a focus on the necessary compromise between adverse events and tumor control, are often effective and allows for uninterrupted, full-dose therapy with targeted agents. Quality of life does not appear deteriorated, rather improved due to efficacy in prolonging wellness.     

胃癌相关核心基因的生物信息学分析

目的：筛选胃癌相关的核心基因及其与胃癌诊断、预后的关系,为胃癌分子诊断、靶向治疗、预后评判提供研究方向。方法：从基因表达数据库（GEO）下载胃癌相关的mRNA表达谱芯片数据,利用R软件的Limma包分别筛选出胃癌组织中较癌旁组织相比具有显著差异表达的基因（DEGs）,在基因功能注释数据库（DAVID）中对DEGs进行基因本体（GO）功能注释及京都基因与基因组百科全书（KEGG）富集分析,交互基因检索工具（STRING）及Cytoscape软件的网络分析插件CytoHubba用于构建蛋白互作网络（PPI）并进行可视化分析,筛选出核心基因;利用生存分析工具（KM数据库）分析核心基因与胃癌患者预后的关系,并量化具有预后意义的核心基因的诊断价值,利用GraphPad软件将其可视化。最后用皮尔逊（Pearson）法检验核心基因之间的相关性。结果：在GEO数据库得到的3个基因芯片表达谱中,胃癌组织与正常组织差异表达显著的基因有1 839个,上调基因851个,下调基因988个,三者取交集后,在3个表达谱芯片中均有显著差异表达的基因有66个,上调基因24个,下调基因42个;GO富集分析显示,差异表达基因的功能主要集中在细胞外空间、细胞外外泌体、消化、细胞外基质组织、胶原纤维组织;KEGG富集分析提示,差异表达基因的通路主要涉及蛋白质消化和吸收、胃酸分泌、氮代谢、ECM-受体相互作用、矿物质吸收等;PPI网络中,Cytoscape可视化分析发现10个核心基因的差异表达与胃癌的发生密切相关,KM数据库检索发现,FN1、COL1A1低表达组患者预后更佳,高表达组更差。FN1、COL1A1的AUC分别为0.93、0.90,提示两者均具有较高的诊断价值,两者的相关性分析得出相关系数r=0.59（P < 0.05）,提示COL1A1与FN1两者在胃癌中的表达呈正相关。结论：生物信息分析筛选的核心基因FN1、COL1A1可能成为提示胃癌患者预后、早期诊断、研发胃癌靶向药物的候选标志物或靶点。