Targeting the ERK signaling pathway in cancer therapy

The extracellular signal-regulated kinase (ERK) signaling pathway is a major determinant in the control of diverse cellular processes such as proliferation, survival, differentiation and motility. This pathway is often up-regulated in human tumors and as such represents an attractive target for the development of anticancer drugs. Because of its multiple roles in the acquisition of a complex malignant phenotype, specific blockade of the ERK pathway is expected to result in not only an anti-proliferative effect but also in anti-metastatic and anti-angiogenic effects in tumor cells. Recently potent small-molecule inhibitors targeting the components of the ERK pathway have been developed. Among them, BAY 43-9006 (Raf inhibitor), and PD184352, PD0325901 and ARRY-142886 (MEK1/2 inhibitors) have reached the clinical trial stage. We briefly discuss the possibility that combination of ERK pathway inhibitors (cytostatic agents) and conventional anticancer drugs (cytotoxic agents) provides an excellent basis for the development of new chemotherapeutic strategies against cancer.     

联合抑制Notch2和MEK/ERK通路对胃癌细胞增殖的影响

目的探讨Notch2和MEK/ERK信号通路在胃癌细胞SGC-7901中是否存在交叉作用。方法采用体外化学合成的特异性针对Notch2的siRNA(Notch2siRNA)和丝裂原激活蛋白激酶(MEK)/细胞外信号调节激酶(ERK)信号通路的抑制剂PD98059,分别单独和联合处理体外培养的胃癌SGC-7901细胞,以转染阴性对照siRNA(control siRNA)细胞作为siRNA对照组,并设不给予任何转染的空白对照组。免疫印迹(Western Blotting)法检测磷酸化ERK1/2(p-ERK)1/2和Notch2蛋白的表达水平。比色法(MTT)检测癌细胞增殖抑制率。结果Notch2siRNA能降低蛋白Notch2的表达水平,并抑制癌细胞增殖[(38.26±1.82)%],而p-ERK的表达水平则较对照组增加。PD98059能降低p-ERK的表达水平,并抑制癌细胞的增殖[(30.05±3.16)%],Notch2水平则无明显变化,联合应用Notch2siRNA和PD98059能明显降低p-ERK和Notch2蛋白的表达水平,与Notch2siRNA或PD98059单独应用比较,显著抑制癌细胞增殖率,差异有统计学意义[(72.55±5.30)%,P0.01]。结论特异性抑制Notch2信号通路,且抑制MEK/ERK通路可进一步增强抑制Notch2通路的抗肿瘤增殖效果,提示MEK/ERK和Notch2 2条信号通路在胃癌SGC-7901细胞中存在交叉作用。     

Notch1信号通路在乳腺癌中的研究进展

乳腺癌是女性最常见、死亡率最高的恶性肿瘤之一,近年来其发病率不断升高。研究发现Notch1信号通路在乳腺癌中起着重要的作用。研究发现Notch1在正常乳腺组织和乳腺良性病变以及乳腺癌中均有表达,在乳腺浸润性导管癌中的表达率明显高于导管原位癌,其表达与乳腺癌HER-2亚型有关,在HER-2阳性型中的Notch1的阳性表达率明显高于其他亚型。研究认为Notch1阳性表达率高与其乳腺癌的分化程度低、分期晚、淋巴结转移阳性率高以及脑转移有关,预示着乳腺癌的预后差,并被认为可作为判断预后的临床指标。此外研究发现Notch1的高表达可导致乳腺癌对阿霉素与紫杉醇的耐药。研究发现Notch1高表达与乳腺癌侵袭强、凋亡抑制有关。研究还发现Notch1的表达影响乳腺癌干细胞的数量,是维持乳腺癌干细胞恶性表型的重要因子。且Notch1与VEGF、c-myc、CCL2、TRB3、MMP2等相关基因表达及肿瘤微环境相关。针对Notch1的靶向治疗的研究有Notch1单克隆抗体、三氧化二砷以及金雀异黄素等药物,以及Notch1相关通路的靶向治疗药物,均可抑制乳腺癌细胞的生长,对乳腺癌有抗肿瘤作用。     

Wnt信号通路与卵巢癌治疗新进展

Wnt通路是一条高度保守的传导通路,Wnt信号通路异常激活与肿瘤发生发展有密切关系。近年来,不少研究证明卵巢癌中存在异常激活的Wnt通路信号蛋白。该文复习了卵巢癌与Wnt通路相关的新近研究进展,对Wnt信号通路、其在卵巢癌发生发展的作用及Wnt通路中潜在的卵巢癌治疗新靶点做一综述,旨在为卵巢癌的临床治疗提供新思路。     

Hedgehog信号通路在白血病中的研究进展

Hedgehog信号通路是人体内的重要信号通路之一.人类Hedgehog信号通路在胚胎发育、组织器官形成及维持机体内环境稳定等生理过程中发挥重要作用,同时与肿瘤的发生和发展也有着密切的关系.新近研究发现Hedgehog信号通路异常活化与血液肿瘤的发生、发展密切相关.现从Hedgehog信号通路的组成,其与造血调控及白血病的关系,以及针对Hedgehog信号通路的靶向治疗等方面,就近年来,Hedgehog信号通路及Hedgehog信号通路抑制剂在白血病的研究进展综述如下.     

Recent advances in the development of nanoparticles for multimodality imaging and therapy of cancer

This review explores recent work directed toward the development of nanoparticles (NPs) for multimodality cancer imaging and targeted cancer therapy. In the growing era of precision medicine, theranostics, or the combined use of targeted molecular probes in diagnosing and treating diseases is playing a particularly powerful role. There is a growing interest, particularly over the past few decades, in the use of NPs as theranostic tools due to their excellent performance in receptor target specificity and reduction in off-target effects when used as therapeutic agents. This review discusses recent advances, as well as the advantages and challenges of the application of NPs in cancer imaging and therapy.     

介入手术护理配合路径图在肿瘤介入治疗中的应用

目的提高肿瘤介入手术护理配合质量。方法结合肿瘤介入手术患者住院时间短、科室手术多、接台时间短的实际情况，将肿瘤患者需求和规范的临床护理行为制作成肿瘤介入手术护理配合路径图。结果提高了肿瘤介入手术患者的满意度及手术换台速度；缩短了患者手术等候时间。结论手术护理配合路径图的应用，可以提高肿瘤介入手术护理配合质量。     

Metastatic Melanoma: Insights Into the Evolution of the Treatments and Future Challenges

Melanoma is the deadliest form of skin cancer. While associated survival prognosis is good when diagnosed early, it dramatically drops when melanoma progresses into its metastatic form. Prior to 2011, the favored therapies include interleukin‐2 and chemotherapies, regardless of their low efficiency and their toxicity. Following key biological findings, two new types of therapy have been approved. First, there are the targeted therapies, which rely on small molecule B‐Raf and MEK inhibitors and allow the treatment of patients with B‐Raf mutated melanoma. Second, there are the immunotherapies, with anti‐CTLA‐4 and anti‐PD‐1 antibodies that are used for patients harboring a B‐Raf wild‐type status. Both approaches have significantly improved patient survival, compared with alkylating agents, in the treatment of unresectable melanoma. Herein, we review the evolution of the treatment of melanoma starting from early discoveries to current therapies. A focus will be provided on drug discovery, synthesis, and mode of action of relevant drugs and the future directions of the domain to overcome the emergence of the resistance events.     

Mechanical allodynia but not thermal hyperalgesia is impaired in mice deficient for ERK2 in the central nervous system

Extracellular signal-regulated kinase (ERK) plays critical roles in pain plasticity. However, the specific contribution of ERK2 isoforms to pain plasticity is not necessarily elucidated. Here we investigate the function of ERK2 in mouse pain models. We used the Cre-loxP system to cause a conditional, region-specific, genetic deletion of Erk2. To induce recombination in the central nervous system, Erk2-floxed mice were crossed with nestin promoter-driven cre transgenic mice. In the spinal cord of resultant Erk2 conditional knockout (CKO) mice, ERK2 expression was abrogated in neurons and astrocytes, but indistinguishable in microglia compared to controls. Although Erk2 CKO mice showed a normal baseline paw withdrawal threshold to mechanical stimuli, these mice had a reduced nociceptive response following a formalin injection to the hind paw. In a partial sciatic nerve ligation model, Erk2 CKO mice showed partially restored mechanical allodynia compared to control mice. Interestingly, thermal hyperalgesia was indistinguishable between Erk2 CKO and control mice in this model. In contrast to Erk2 CKO mice, mice with a targeted deletion of ERK1 did not exhibit prominent anomalies in these pain models. In Erk2 CKO mice, compensatory hyperphosphorylation of ERK1 was detected in the spinal cord. However, ERK1 did not appear to influence nociceptive processing because the additional inhibition of ERK1 phosphorylation using MEK (MAPK/ERK kinase) inhibitor SL327 did not produce additional changes in formalin-induced spontaneous behaviors in Erk2 CKO mice. Together, these results indicate that ERK2 plays a predominant and/or specific role in pain plasticity, while the contribution of ERK1 is limited.     

Targeting metabolism: A potential strategy for hematological cancer therapy

Most hematological cancer-related relapses and deaths are caused by metastasis; thus, the importance of this process as a target of therapy should be considered. Hematological cancer is a type of cancer in which metabolism plays an essential role in progression. Therefore, we are required to block fundamental metastatic processes and develop specific preclinical and clinical strategies against those biomarkers involved in the metabolic regulation of hematological cancer cells, which do not rely on primary tumor responses. To understand progress in this field, we provide a summary of recent developments in the understanding of metabolism in hematological cancer and a general understanding of biomarkers currently used and under investigation for clinical and preclinical applications involving drug development. The signaling pathways involved in cancer cell metabolism are highlighted and shed light on how we could identify novel biomarkers involved in cancer development and treatment. This review provides new insights into biomolecular carriers that could be targeted as anticancer biomarkers.     

Targeting the interaction of Aurora kinases and SIRT1 mediated by Wnt signaling pathway in colorectal cancer: A critical review

The Aurora kinases belong to the family of serine/threonine kinase, a central regulator of mitosis and their expression increased during G2/M phase. It is classified into Aurora A, B and C, each has distinct roles in cellular processes, which includes regulation of spindle assembly, function of centrosomes, cytoskeleton and cytokinesis. During cancer growth, their rapid increase makes most attractive marker for cancer treatment at present. However Aurora A kinase is known to be a marker for cancer therapy, the most important serine/threonine kinase of Aurora B kinase involvement in cancer is still inadequate. Subsequently, the recent findings revealed that the class III histone deacetylase of SIRT1 is a key regulator to activate Aurora kinases from S phase damaged DNA through Wnt signaling pathway. Even if both Aurora A kinase and SIRT1 serve as a marker for cancer therapy, the present review reveals it is interaction in Wnt signaling pathway that solely for colorectal cancer.     

前列腺癌分子影像学诊断与治疗进展

前列腺癌严重威胁着男性健康,近年来我国前列腺癌的发病率也迅速增加,早期发现前列腺癌对于提高生存率具有十分积极的意义。目前各前列腺癌指南中仍需通过超声引导下的前列腺活检确诊,再通过主动监测、根治性切除术、放疗及局部放疗等手段进行治疗。但前列腺活检增加了尿潴留、血尿等不必要的风险,还会遗漏多达1/3的癌组织,且目前的治疗方法因缺乏特异性而对患者进行过度或不足的治疗。近年来,对前列腺癌的诊断和治疗已经迈入分子水平,通过分子影像学进行无创精准的诊断和治疗展现出巨大的发展前景。本文将从核医学分子成像、MR分子成像、光学分子成像、超声分子成像4种常见分子影像学技术在前列腺癌的应用进展进行回顾并作一综述。     

Beyond cancer cells: Targeting the tumor microenvironment with gene therapy and armed oncolytic virus

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环指蛋白157通过下调小凹蛋白-1表达参与ERK通路激活促进黑素瘤细胞增殖

目的 探讨环指蛋白157(RING finger protein 157, RNF157)在黑素瘤细胞增殖中的作用及相关机制。方法采用慢病毒转染技术构建RNF157过表达黑素瘤细胞株，小干扰RNA(siRNA)技术构建敲减RNF157的黑素瘤细胞株，采用实时荧光定量聚合酶链反应（qRT-PCR）和Western印迹实验验证转染效果。采用MTT实验、克隆形成实验检测RNF157过表达黑素瘤细胞和敲减RNF157黑素瘤细胞的细胞增殖能力。采用裸鼠皮下成瘤实验及免疫组化染色检测RNF157过表达黑素瘤细胞体外增殖能力。采用免疫共沉淀（Co-IP）结合质谱分析、蛋白质组学和泛素化组学，探究RNF157在ERK通路中的潜在作用机制。结果 免疫组化染色结果显示，RNF157在黑素瘤组织中的表达高于瘤旁组织（P<0.01）。qRT-PCR和Western印迹实验结果显示，过表达组的RNF157表达水平显著高于对照组（P<0.000 1）;si3转染效率最高，si3组的RNF157表达水平显著低于对照组（P<0.01）。MTT实验、克隆形成实验结果显示，RNF157过表达可促进黑素瘤...     

Recent insights in the PI3K/Akt pathway as a promising therapeutic target in combination with EGFR-targeting agents to treat head and neck squamous cell carcinoma

Resistance to therapies targeting the epidermal growth factor receptor (EGFR), such as cetuximab, remains a major roadblock in the search for effective therapeutic strategies in head and neck squamous cell carcinoma (HNSCC). Due to its close interaction with the EGFR pathway, redundant or compensatory activation of the phosphatidylinositol 3-kinase (PI3K)/Akt pathway has been proposed as a major driver of resistance to EGFR inhibitors. Understanding the role of each of the main proteins involved in this pathway is utterly important to develop rational combination strategies able to circumvent resistance. Therefore, the current work reviewed the role of PI3K/Akt pathway proteins, including Ras, PI3K, tumor suppressor phosphatase and tensing homolog, Akt and mammalian target of rapamycin in resistance to anti-EGFR treatment in HNSCC. In addition, we summarize PI3K/Akt pathway inhibitors that are currently under (pre)clinical investigation with focus on overcoming resistance to EGFR inhibitors. In conclusion, genomic alterations in and/or overexpression of one or more of these proteins are common in both human papillomavirus (HPV)-positive and HPV-negative HNSCC tumors. Therefore, downstream effectors of the PI3K/Akt pathway serve as promising drug targets in the search for novel therapeutic strategies that are able to overcome resistance to anti-EGFR treatment. Co-targeting EGFR and the PI3K/Akt pathway can lead to synergistic drug interactions, possibly restoring sensitivity to EGFR inhibitors and hereby improving clinical efficacy. Better understanding of the predictive value of PI3K/Akt pathway alterations is needed to allow the identification of patient populations that might benefit most from these combination strategies.     

Molecular targets for cancer therapy in the PI3K/AKT/mTOR pathway

Aberrations in various cellular signaling pathways are instrumental in regulating cellular metabolism, tumor development, growth, proliferation, metastasis and cytoskeletal reorganization. The fundamental cellular signaling cascade involved in these processes, the phosphatidylinositol 3-kinase/protein kinase-B/mammalian target of rapamycin (PI3K/AKT/mTOR), closely related to the mitogen-activated protein kinase (MAPK) pathway, is a crucial and intensively explored intracellular signaling pathway in tumorigenesis. Various activating mutations in oncogenes together with the inactivation of tumor suppressor genes are found in diverse malignancies across almost all members of the pathway. Substantial progress in uncovering PI3K/AKT/mTOR alterations and their roles in tumorigenesis has enabled the development of novel targeted molecules with potential for developing efficacious anticancer treatment. Two approved anticancer drugs, everolimus and temsirolimus, exemplify targeted inhibition of PI3K/AKT/mTOR in the clinic and many others are in preclinical development as well as being tested in early clinical trials for many different types of cancer. This review focuses on targeted PI3K/AKT/mTOR signaling from the perspective of novel molecular targets for cancer therapy found in key pathway members and their corresponding experimental therapeutic agents. Various aberrant prognostic and predictive biomarkers are also discussed and examples are given. Novel approaches to PI3K/AKT/mTOR pathway inhibition together with a better understanding of prognostic and predictive markers have the potential to significantly improve the future care of cancer patients in the current era of personalized cancer medicine.     

Targeting tumors with nanobodies for cancer imaging and therapy

The use of monoclonal antibodies has revolutionized both cancer therapy and cancer imaging. Antibodies have been used to directly inhibit tumor cell proliferation or to target drugs to tumors. Also in molecular imaging, monoclonal antibodies have found their way to the clinic. Nevertheless, distribution within tumors is hampered by their size, leading to insufficient efficacy of cancer treatment and irregular imaging. An attractive alternative for monoclonal antibodies are nanobodies or VHHs. These are the variable domain of heavy-chain antibodies from animals from the Camelidae family that were first discovered in 1993. Stimulated by the ease of nanobody selection, production, and low immunogenicity potential, a number of nanobodies specific to different disease-related targets have been developed. For cancer therapy, nanobodies have been employed as antagonistic drugs, and more recently, as targeting moieties of effector-domaINS and of drug delivery systems. In parallel, nanobodies have also been employed for molecular imaging with modalities such as nuclear and optical imaging. In this review, we discuss recent developments in the application of nanobodies as targeting moieties in cancer therapy and cancer imaging. With such a wide range of successful applications, nanobodies have become much more than simple antagonists.     

不同化疗药物介入干预环境下对肝癌细胞系的敏感性

目的检测不同浓度梯度的高浓度化疗药物持续作用不同时间对肝癌细胞系HepG-2的作用,并探索化疗药物有无浓度、时间饱和现象。方法每种化疗药选择5个浓度及四个时间段,采用MTT法分别检测不同浓度及作用时间的8种化疗药物对体外培养的HepG-2细胞的抑制率。结果各种药物不同作用浓度及时间对肝癌细胞系有不同的抑制度;对于任一药物而言,作用浓度—时间之间存在关联,每种药物均有其饱和浓度及作用时间。结论不同化疗药物有其最佳时间—浓度曲线;可以据此优化化疗方案;实现介入治疗个体剂量精确化。