肺癌分子靶向治疗的现状与进展

分子靶向药物是利用肿瘤细胞和正常细胞之间分子细胞生物学上的差异,采用封闭受体、抑制血管生成、阻断信号传导通路等方法作用于肿瘤细胞的特定靶点,特异性地抑制肿瘤细胞的生长,促使肿瘤细胞凋亡。分子靶向治疗比传统的化疗特异性强,不良反应小,将成为以后肿瘤治疗的新趋势。     

肺癌分子靶向治疗的现状与进展

分子靶向药物是利用肿瘤细胞和正常细胞之间分子细胞生物学上的差异,采用封闭受体、抑制血管生成、阻断信号传导通路等方法作用于肿瘤细胞的特定靶点,特异性地抑制肿瘤细胞的生长,促使肿瘤细胞凋亡。分子靶向治疗比传统的化疗特异性强,不良反应小,将成为以后肿瘤治疗的新趋势。     

您知道什么是分子靶向治疗吗?

"分子靶向治疗"这一名词近年来频繁出现于各类肿瘤相关的新闻中,成为目前继手术、化疗、放疗等三大常规治疗之后最热门的肿瘤治疗方法,是肿瘤治疗领域具有里程碑意义的进步。其实所谓的"分子靶向治疗",简单的说就是通过干预肿瘤细胞所特有的靶点,达到抑制肿瘤的目的。     

乳腺癌分子靶向治疗研究新进展

乳腺癌分子靶向治疗是指针对与乳腺癌发生发展有关的癌基因及其表达产物进行治疗的一种方法。分子靶向药物通过阻断肿瘤细胞或相关细胞的信号传导,来控制相应细胞的基因表达,从而抑制肿瘤细胞的     

肿瘤的靶向治疗

靶向治疗是针对肿瘤细胞恶性表型的分子靶点,作用于促进肿瘤生长、存活的特异性细胞受体、信号传导等通道,实现抑制肿瘤细胞生长或促进凋亡的抗肿瘤作用。新的靶向治疗药物rituximab、伊马替尼、赫赛汀和全反式维甲酸已开始用于临床治疗,本文综述这些药物的作用机制、适应证、疗效及安全性。与传统细胞毒化疗不同,肿瘤靶向治疗具有特异性抗肿瘤作用,并且毒性明显减少。肿瘤靶向治疗令人鼓舞的初步成果为其进一步发展奠定了基础,提供了典范,开创了肿瘤化疗的新领域。     

HSP90抑制剂在肿瘤临床中的研究进展

0 引言 分子靶向抗肿瘤治疗是目前肿瘤治疗研究领域的热点,并取得了令人瞩目的疗效.最著名的例子是BCR-ABL特异性抑制剂格列卫在慢性髓系白血病中的应用[1].作为靶点的分子通常是与致癌信号通路相关的蛋白激酶,但是研究发现单个蛋白激酶分子的靶向治疗通常只对少数肿瘤细胞有效,而且敏感的肿瘤细胞通常会发展为获得性抵抗.分子靶向治疗的最新进展提示有效的控制肿瘤需要同时抑制多个致癌信号通道[2].HSP90是一类普遍存在于各种细胞的分子伴侣蛋白,在肿瘤细胞中,HSP90通过调节多种癌蛋白的功能,从而参与调节肿瘤细胞的增殖、生存、侵袭、转移和血管生成等多种重要过程.由于HSP90对多种癌蛋白具有调控作用,通过对HSP90的抑制可以实现同时对多种肿瘤信号通路的调控,从而有效控制肿瘤.HSP90抑制剂的开发研究已经成为分子靶向抗肿瘤治疗的一个热点,近年来国外大量研究开发出了多种HSP90抑制剂,本文对HSP90抑制剂在多种肿瘤的临床研究进展讲行综述.     

分子靶向治疗在妇科恶性肿瘤中的研究进展

分子靶向治疗（molecular targeted therapy,MTT）作为肿瘤治疗的新手段,通过特异性靶向肿瘤发生发展中起关键作用的分子或相关细胞的信号转导通路控制细胞基因表达,从而抑制或杀死癌细胞,基于对细胞分子生物学及信号转导机制,在分子水平上对肿瘤细胞进行直接或间接的精确打击。肿瘤分子靶向治疗因其具有疗效高、不良反应低的特点而备受瞩目,其出现为肿瘤的治疗开辟了新的领域和广阔的前景。本文就妇科恶性肿瘤中分子靶向治疗的研究进展进行综述。      

肿瘤药物靶向治疗的最新进展

肿瘤药物的靶向治疗是以已知肿瘤发生中涉及的异常分子和基因为靶点而设计和研制的药物。实践证明,肿瘤靶向药物治疗为乳腺癌、肠癌、肺癌等多种恶性肿瘤的治疗提供了新的有效方法。肿瘤靶向药物分为肿瘤细胞单克隆抗体和抑制肿瘤细胞增殖的靶向药物,其中前者又包括抗肿瘤单抗药物和抗肿瘤单抗偶联物。本文对肿瘤抗体介导的靶向治疗药物的应用现状作一阐述。     

晚期进展期非小细胞肺癌治疗进展

晚期非小细胞肺癌的一线治疗主要应用以铂类为基础的两药联合的第3代化疗方案.多西紫杉醇或培美曲塞的单药治疗为二线治疗.分子靶向治疗是利用肿瘤细胞与正常细胞之间分子生物学上的差异而作用于肿瘤细胞的特定靶点,特异性抑制肿瘤细胞生长,促使肿瘤细胞凋亡.分子靶向药物包括表皮生长因子受体拮抗剂、血管生成抑制剂和信号传导抑制剂等.随着药物治疗的进展,耐药问题同样引起了人们关注.     

凋亡与肿瘤靶向治疗

凋亡异常与肿瘤发生密切相关.由于凋亡过程受基因调控,所以肿瘤对靶向凋亡调控基因的治疗是敏感的.一种靶向凋亡治疗肿瘤的策略已经形成,方法包括通过活化肿瘤细胞内的凋亡分子和引入外源性促凋亡分子直接诱导凋亡;通过阻断生存信号的传导间接诱导凋亡.     

PKC 412 small-molecule tyrosine kinase inhibitor: single-compound therapy for pancreatic cancer

BACKGROUND: PKC412 is a kinase inhibitor that blocks protein kinase C (PKC), vascular endothelial growth factor receptors, platelet-derived growth factor receptor FLT3, and other class III receptor tyrosine kinases. The enthusiasm for this compound is based on its inhibitory effect even in the case of FLT3 mutations. The aim of this study was to analyze the role of FLT3 in pancreatic cancer and to study the biological activity of combined inhibition of neovascularization and mitogenesis in this disease. METHODS: FLT3 expression was analyzed in 18 pancreatic cancer specimens by real-time quantitative polymerase chain reaction (RTQ-PCR) and immunohistochemistry. Sixteen pancreatic cancer cell lines were screened for ITD and D835 point mutations of the FLT3 gene. MTT assays and anchorage-independent growth assays were used to study cell growth. Flow cytometry was used for cell cycle analysis and apoptosis quantification. In vivo AsPC-1 and HPAF-II cells were used for orthotopic tumor modeling. Immunohistochemistry was used to quantify tumor angiogenesis. RESULTS: FLT3 expression is down-regulated in pancreatic cancer. Activating FLT3 mutations (ITD, D835) were not detectable in any of the pancreatic cancer cell lines. Cell growth was significantly inhibited as cell-cycle progression was reduced and programmed cell death increased. In vivo PKC412 therapy resulted in a significant inhibition of orthotopic tumor growth with abrogation of tumor angiogenesis. CONCLUSIONS: These data highlight that PKC412 may be a new compound in target therapy of inoperable pancreatic cancer patients and suggest a potential role for the combined use of broad spectrum kinase inhibitors in the management of these patients.     

Blocked pathways: FTIs shut down oncogene signals

Ras proteins play fundamental roles in cell signal transduction pathways that regulate cell growth, differentiation, proliferation, and survival. ras mutations are among the most frequently encountered genetic abnormalities in human cancers and play a key role in tumorigenesis. The enzymatic attachment of a 15- or 20-carbon moiety to the Ras protein through farnesylation or geranylgeranylation, respectively, is a required step in the proper localization and activation of Ras. Inhibition of the catalytic enzymes, farnesyl transferase and geranylgeranyl transferase, is a novel, mechanism-based, targeted approach to cancer therapy development. Geranylgeranyl transferase inhibitors suppress tumor growth by accumulating cells in the G(1)/S cell cycle phase. One mechanism by which farnesyl transferase inhibitors suppress tumor growth is by inhibiting bipolar spindle formation, thereby blocking progression from prophase to metaphase. Although the exact molecular target responsible for the antitumor activity of farnesyl transferase inhibitors is unclear, at least in some tumor cells, inhibition of phosphoinositide-3-OH kinase/Akt-mediated cell survival pathways may play a critical role. Identifying the farnesylated proteins that are targeted by farnesyl transferase inhibitors and the tumor molecular signatures that dictate which set of patients will respond to farnesyl transferase inhibitors are critical end points for future mechanistic studies.     

Recent developments and future perspectives of personalized oncology

Increasing understanding of molecular carcinogenesis has begun to change paradigms in oncology. On the diagnostic side, the characterization of key mutations and molecular pathways responsible for tumor development and progression has led to the identification of a large number of potential targets for diagnostic and therapeutic intervention. On the treatment and prevention side, molecular analysis will be of even greater importance for guiding individualized therapy. Diagnostics of molecular lesions present in each tumor will become a key feature of future clinical care. This will allow prediction of response with substantially increased accuracy, stratification of particular patient groups, and eventually personalization of therapy. Striking examples of molecular targeted therapies that have already been established in clinical practice include tyrosine kinase inhibitors in chronic myelogenous leukemia and gastrointestinal stromal tumors, epidermal growth factor receptor (EGFR) inhibition in EGFR-mutated lung cancer, HER2/neu blockade in HER2/neu-positive breast cancer, and anaplastic lymphoma kinase (ALK) inhibitors in lung cancer with EML4-ALK fusion. The scientific development along this line will change the approach to tumor diseases in the future. Patients will be treated according to the specific molecular profiles found in the individual tumor tissue and preferentially with targeted substances, if available.     

Noninvasive Imaging Reveals Inhibition of Ovarian Cancer by Targeting CXCL12-CXCR4

Patients with metastatic ovarian cancer continue to have a dismal prognosis, emphasizing the need for new strategies to identify and develop new molecular targets for therapy. Chemokine CXCL12 and its receptor CXCR4 are upregulated in metastatic ovarian cancer cells and the intraperitoneal tumor microenvironment. CXCL12-CXCR4 signaling promotes multiple steps in proliferation and dissemination of ovarian cancer cells, suggesting that targeted inhibition of this pathway will limit tumor progression. To investigate CXCL12-CXCR4 signaling in ovarian cancer and establish effects of inhibiting this pathway on tumor progression and survival, we designed a Gaussia luciferase complementation imaging reporter system to detect CXCL12 binding to CXCR4 in ovarian cancer cells. In cell-based assays, we established that the complementation imaging reporter could detect CXCL12 binding to CXCR4 and quantify specific inhibition of ligand-receptor interaction. We monitored CXCL12-CXCR4 binding and inhibition in a mouse xenograft model of metastatic human ovarian cancer by imaging Gaussia luciferase complementation and assessed tumor progression with firefly luciferase. Bioluminescence imaging studies in living mice showed that treatment with AMD3100, a clinically approved inhibitor of CXCL12-CXCR4, blocked ligand-receptor binding and reduced growth of ovarian cancer cells. Treatment with AMD3100 also modestly improved overall survival of mice with metastatic ovarian cancer. The Gaussia luciferase complementation imaging reporter system will facilitate further preclinical development and optimization of CXCL12-CXCR4 targeted compounds for treatment of ovarian cancer. Our research supports clinical translation of existing CXCR4 inhibitors for molecular therapy for ovarian cancer.     

JAK–STAT inhibition impairs K-RAS-driven lung adenocarcinoma progression

Oncogenic K-RAS has been difficult to target and currently there is no K-RAS-based targeted therapy available for patients suffering from K-RAS-driven lung adenocarcinoma (AC). Alternatively, targeting K-RAS-downstream effectors, K-RAS-cooperating signaling pathways or cancer hallmarks, such as tumor-promoting inflammation, has been shown to be a promising therapeutic strategy. Since the JAK–STAT pathway is considered to be a central player in inflammation-mediated tumorigenesis, we investigated here the implication of JAK–STAT signaling and the therapeutic potential of JAK1/2 inhibition in K-RAS-driven lung AC. Our data showed that JAK1 and JAK2 are activated in human lung AC and that increased activation of JAK–STAT signaling correlated with disease progression and K-RAS activity in human lung AC. Accordingly, administration of the JAK1/2 selective tyrosine kinase inhibitor ruxolitinib reduced proliferation of tumor cells and effectively reduced tumor progression in immunodeficient and immunocompetent mouse models of K-RAS-driven lung AC. Notably, JAK1/2 inhibition led to the establishment of an antitumorigenic tumor microenvironment, characterized by decreased levels of tumor-promoting chemokines and cytokines and reduced numbers of infiltrating myeloid derived suppressor cells, thereby impairing tumor growth. Taken together, we identified JAK1/2 inhibition as promising therapy for K-RAS-driven lung AC.     

Methionine deprivation inhibits glioma growth through downregulation of CTSL

The metabolism of tumor cells is characterized by the regulation of demand, nutrient supply and metabolic enzymes, which are different in cancer tissues from those in corresponding healthy tissues. There is growing evidence that dietary composition influences biological processes that contribute to tumor incidence and progression as much as genetic status. One possibility for specific dietary interventions in cancer patients is to limit methionine intake. The role of methionine metabolism in tumors suggests that interference with the methionine metabolism network by either drug or environmental effects may show substantial therapeutic effects, but the molecular mechanism is not completely clear. In this study, methionine deprivation was found to downregulate cathepsin L (CTSL) and induce proliferation inhibition in glioma cells. We also demonstrated that CTSL is a tumor-related gene, and promotes the proliferation and invasion of glioma. Our results showed that the treatment of methionine metabolism and CTSL related genes in glioma cells may be a novel strategy for glioma therapy in the future.     

Indoleamine-2,3-dioxygenase, an immunosuppressive enzyme that inhibits natural killer cell function, as a useful target for ovarian cancer therapy

This study examined the role of the immuno-suppressive enzyme indoleamine-2,3-dioxygenase (IDO) in ovarian cancer progression, and the possible application of this enzyme as a target for ovarian cancer therapy. We transfected a short hairpin RNA vector targeting IDO into the human ovarian cancer cell line SKOV-3, that constitutively expresses IDO and established an IDO downregulated cell line (SKOV-3/shIDO) to determine whether inhibition of IDO mediates the progression of ovarian cancer. IDO downregulation suppressed tumor growth and peritoneal dissemination in vivo, without influencing cancer cell growth. Moreover, IDO downregulation enhanced the sensitivity of cancer cells to natural killer (NK) cells in vitro, and promoted NK cell accumulation in the tumor stroma in vivo. These findings indicate that downregulation of IDO controls ovarian cancer progression by activating NK cells, suggesting IDO targeting as a potential therapy for ovarian cancer.     

循环肿瘤细胞的异质性在转移性乳腺癌中的作用研究进展

循环肿瘤细胞（CTC）的计数可以预测转移性乳腺癌的预后,但其改善患者预后的能力在临床试验中尚未得到证实。目前研究专注于CTC的分子表征,作为肿瘤组织的“替代物”以非侵入性地方式评估癌症基因组表达及其在治疗过程中的演变。CTC中存在上皮-间质转化过程（EMT）,其特点为上皮标志物的缺失。EMT过程可以存在于侵袭性及耐药性较强的细胞,其计数和表征,能够引起肿瘤的复发和进展,具有较高的临床价值。本文深入探讨循环肿瘤细胞的异质性及在转移性乳腺癌上皮-间质转化过程中的作用。使其成为乳腺癌患者监测转移和预后的常规的检测指标,并有助于明确转移的机制,更有望发现乳腺癌转移治疗的新靶点。     

PD-1/PD-L1信号通路在结直肠癌免疫逃逸及其治疗中作用的研究进展

结直肠癌是常见的消化系统肿瘤。近年来,免疫治疗是继放化疗及靶向治疗之后,结直肠癌治疗领域的新方向。而作为T细胞免疫反应的协同刺激信号通路,程序性死亡分子1（programmed death-1,PD-1）/PD-1配体（PD-1 ligand,PD-L1)信号通路在肿瘤的免疫治疗中起着至关重要的作用。PD-1/PD-L1信号通路被激活后,可参与肿瘤的免疫逃逸,与肿瘤的发生、发展密切相关。体内外实验证实,阻断该通路可增强机体内源性抗肿瘤免疫效应。本文就PD-1/PD-L1信号通路及其阻滞剂在结直肠癌领域中的研究进展作一综述。