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miR-16-5p enhances sensitivity to RG7388 through targeting PPM1D expression (WIP1) in Childhood Acute Lymphoblastic Leukemia. miR-16-5p通过靶向儿童急性淋巴细胞白血病中PPM1D表达(WIP1)增强对RG7388的敏感性。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.113
Maryam Zanjirband, Soheila Rahgozar, Narges Aberuyi

Aim: Given the encouraging results of the p53-Mdm2 inhibitor RG7388 in clinical trials and the vital function of miR-16-5p in suppressing cell proliferation, the aim of the present study was to investigate the combined impact of RG7388 and miR-16-5p overexpression on the childhood acute lymphoblastic leukemia (chALL). Methods: miRTarBase and miRDB, along with KEGG and STRING databases, were used to predict miR-16-5p target genes and explore protein-protein interaction networks, respectively. B- and T-lymphoblastic cell lines, in addition to patient primary cells, were treated with RG7388. Ectopic overexpression of miR-16-5p in Nalm6 cell line was induced through cell electroporation and transfection of microRNA mimics was confirmed by qRT-PCR. Cell viability was evaluated using the MTT assay. Western blot analyses were performed to evaluate the effects of RG7388 and miR-16-5p upregulation on the protein levels of p53 and its downstream target genes in chALL cells. Paired sample t-test was employed for statistical analyses. Results: MTT assay showed RG7388-induced cytotoxicity in wild-type p53 Nalm6 cell line and p53 functional patient primary cells. However, CCRF-CEM and p53 non-functional leukemic cells indicated drug resistance. Western blot analyses validated the bioinformatics results, confirming the downregulation of WIP1, p53 stabilization, as well as overexpression of p21WAF1 and Mdm2 proteins in Nalm6 cells transfected with miR-16-5p. Moreover, enhanced sensitivity to RG7388 was observed in the transfected cells. Conclusion: This is the first study indicating the mechanistic importance of miR-16-5p overexpression in chALL and its inhibitory role in leukemia treatment when combined with the p53-Mdm2 antagonist, RG7388. These findings might be useful for researchers and clinicians to pave the way for better management of chALL.

目的:鉴于p53-Mdm2抑制剂RG7388在临床试验中的令人鼓舞的结果和miR-16-5p在抑制细胞增殖方面的重要功能,本研究的目的是探讨RG7388和miR-16-5p过表达对儿童急性淋巴细胞白血病(chALL)的联合影响。方法:分别使用miRTarBase和miRDB以及KEGG和STRING数据库预测miR-16-5p靶基因并探索蛋白-蛋白相互作用网络。除了患者原代细胞外,还使用RG7388处理B淋巴母细胞和t淋巴母细胞。通过细胞电穿孔诱导Nalm6细胞株中miR-16-5p异位过表达,并通过qRT-PCR证实转染了microRNA模拟物。采用MTT法测定细胞活力。Western blot分析RG7388和miR-16-5p上调对chALL细胞中p53及其下游靶基因蛋白水平的影响。采用配对样本t检验进行统计分析。结果:MTT实验显示rg7388对野生型p53 Nalm6细胞系和p53功能性患者原代细胞均有诱导细胞毒性作用。然而,CCRF-CEM和p53无功能白血病细胞显示耐药。Western blot分析验证了生物信息学结果,证实了转染miR-16-5p的Nalm6细胞中WIP1下调,p53稳定,p21WAF1和Mdm2蛋白过表达。此外,转染的细胞对RG7388的敏感性增强。结论:这是首次研究表明miR-16-5p过表达在chALL中的机制重要性,以及miR-16-5p与p53-Mdm2拮抗剂RG7388联合在白血病治疗中的抑制作用。这些发现可能对研究人员和临床医生为更好地管理chALL铺平道路有用。
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引用次数: 1
Multimodal 4-arylchromene derivatives with microtubule-destabilizing, anti-angiogenic, and MYB-inhibitory activities. 具有微管不稳定、抗血管生成和myb抑制活性的多模态4-芳基铬衍生物。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.90
Leonhard H F Köhler, Sebastian Reich, Maria Yusenko, Karl-Heinz Klempnauer, Gerrit Begemann, Rainer Schobert, Bernhard Biersack

Aim: Efficient and readily available anticancer drugs are sought as treatment options. For this reason, chromene derivatives were prepared using the one-pot reaction and tested for their anticancer and anti-angiogenic properties. Methods: 2-Amino-3-cyano-4-(aryl)-7-methoxy-4H-chromene compounds (2A-R) were repurposed or newly synthesized via a three-component reaction of 3-methoxyphenol, various aryl aldehydes, and malononitrile. We performed assays to study the inhibition of tumor cell growth [3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrazolium bromid (MTT) assay], effects on microtubules (immunofluorescence), cell cycle (flow-activated cell sorting analysis), angiogenesis (zebrafish model), and MYB activity (luciferase reporter assay). Fluorescence microscopy was applied for localization studies via copper-catalyzed azide-alkyne click reaction of an alkyne-tagged drug derivative. Results: Compounds 2A-C and 2F exhibited robust antiproliferative activities against several human cancer cell lines (50% inhibitory concentrations in the low nanomolar range) and showed potent MYB inhibition. The alkyne derivative 3 was localized in the cytoplasm after only 10 min of incubation. Substantial microtubule disruption and G2/M cell-cycle arrest were observed, where compound 2F stood out as a promising microtubule-disrupting agent. The study of anti-angiogenic properties showed that 2A was the only candidate with a high potential to inhibit blood vessel formation in vivo. Conclusion: The close interplay of various mechanisms, including cell-cycle arrest, MYB inhibition, and anti-angiogenic activity, led to identifying promising multimodal anticancer drug candidates.

目的:寻求有效和容易获得的抗癌药物作为治疗选择。为此,采用一锅反应法制备了铬胺衍生物,并对其抗癌和抗血管生成性能进行了测试。方法:以3-甲氧基苯酚、各种芳基醛和丙二腈为原料,经三组分反应,重新利用或合成2-氨基-3-氰-4-(芳基)-7-甲氧基- 4h -铬化合物(2A-R)。我们进行了实验来研究肿瘤细胞生长的抑制[3-(4,5 -二甲基噻唑-2-基)- 2,5 -二苯基溴化四唑(MTT)试验],对微管(免疫荧光)、细胞周期(流动激活细胞分选分析)、血管生成(斑马鱼模型)和MYB活性(荧光素酶报告细胞试验)的影响。利用荧光显微镜对一种炔标记药物衍生物的铜催化叠氮-炔咔嗒反应进行了定位研究。结果:化合物2A-C和2F对几种人类癌细胞系表现出强大的抗增殖活性(在低纳摩尔范围内抑制浓度为50%),并表现出有效的MYB抑制作用。10分钟后,炔衍生物3在细胞质中定位。观察到大量的微管破坏和G2/M细胞周期阻滞,其中化合物2F作为一种有前途的微管破坏剂而突出。抗血管生成特性的研究表明,2A是体内唯一具有高抑制血管形成潜力的候选药物。结论:多种机制的密切相互作用,包括细胞周期阻滞、MYB抑制和抗血管生成活性,导致了有希望的多模式抗癌候选药物的确定。
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引用次数: 1
Fungal mycobiome-mediated immune response: a non-negligible promoter in pancreatic oncogenesis and chemoresistance. 真菌菌群介导的免疫反应:胰腺肿瘤发生和化疗耐药的不可忽视的启动子。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.06
Yaling Jiang, Valentina Donati, Godefridus J Peters, Elisa Giovannetti, Dong Mei Deng

Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal cancers in humans due to late diagnosis and poor response to treatments. The tumor microenvironment (TME) of PDAC is characterized by a distinctive, suppressive immune profile, which inhibits the protective functions of anti-tumor immunity and thereby contributes to PDAC progression. Recently, the study of Alam et al. discovered for the first time that the intratumoral fungal mycobiome could contribute to the recruitment and activation of type 2 immune cells in the TME of PDAC via enhancing the secretion of a chemoattractant, interleukin (IL-) 33. In this article, we reviewed the important findings of this study. Together with our findings, we synthetically discussed the role of the fungal mycobiome in orchestrating the immune response and thereby modulating tumor progression.

胰腺导管腺癌(Pancreatic ductal adenocarcinoma, PDAC)是人类最致命的癌症之一,因其诊断较晚且对治疗反应较差。PDAC的肿瘤微环境(tumor microenvironment, TME)具有独特的抑制免疫特征,抑制抗肿瘤免疫的保护功能,从而促进PDAC的进展。最近,Alam等人的研究首次发现肿瘤内真菌菌群可通过增强一种趋化剂白细胞介素(IL-) 33的分泌,参与PDAC TME中2型免疫细胞的募集和激活。在本文中,我们回顾了本研究的重要发现。结合我们的研究结果,我们综合讨论了真菌菌群在协调免疫反应从而调节肿瘤进展中的作用。
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引用次数: 0
Interaction of pregnane X receptor with hypoxia-inducible factor-1 regulates chemoresistance of prostate cancer cells. 孕激素X受体与缺氧诱导因子-1的相互作用调控前列腺癌细胞的化疗耐药。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.14
Jiuhui Wang, Daotai Nie

Aim: The nuclear pregnane X receptor (PXR) is a pivotal regulator of steroid and xenobiotics metabolism and plays an important role in shaping tumor cell responses to chemotherapy. Hypoxia within tumor tissue has multifaceted effects, including multiple drug resistance. The goal of this study was to determine whether PXR contributes to hypoxia-induced drug resistance. Methods: Metastatic prostate cancer cells were used to study the interaction of PXR and hypoxia-inducible factor-1 (HIF-1 in drug resistance associated with hypoxia. The activities of PXR and HIF-1 were determined by assays for its reporter gene or target gene expression. Co-immunoprecipitation (Co-IP) was used to determine the interaction of PXR and HIF-1. Ablation or inhibition of PXR or HIF-1 was used to determine their roles in hypoxia-induced chemoresistance. Results: PXR was activated by hypoxia, leading to increased expression of multidrug resistance protein 1 (MDR1). Inhibition of PXR by pharmacological compounds or depletion by shRNAs reduced the hypoxic induction of MDR1 and sensitized prostate cancer cells to chemotherapy under hypoxia. HIF-1 was required for PXR activation under hypoxia. Co-immunoprecipitation results showed that HIF-1 and PXR could physically interact with each other, leading to crosstalk between these two transcription factors. Conclusion: PXR contributes to hypoxia-induced drug resistance in prostate cancer cells through its interaction with HIF-1.

目的:核孕激素X受体(nuclear pregnane X receptor, PXR)是类固醇和外源药物代谢的关键调节因子,在形成肿瘤细胞对化疗的反应中起重要作用。肿瘤组织缺氧具有多方面的影响,包括多重耐药。本研究的目的是确定PXR是否与缺氧诱导的耐药有关。方法:采用转移性前列腺癌细胞,研究PXR与缺氧诱导因子-1 (HIF-1)在缺氧相关耐药中的相互作用。通过检测PXR和HIF-1的报告基因或靶基因的表达来测定其活性。采用共免疫沉淀法(Co-IP)测定PXR与HIF-1的相互作用。消融或抑制PXR或HIF-1被用来确定它们在缺氧诱导的化疗耐药中的作用。结果:PXR被缺氧激活,导致多药耐药蛋白1 (MDR1)表达增加。药理化合物抑制PXR或shRNAs耗竭可降低MDR1的缺氧诱导,使前列腺癌细胞对缺氧下的化疗敏感。缺氧条件下PXR的激活需要HIF-1。共免疫沉淀结果显示HIF-1和PXR可以相互作用,导致这两个转录因子之间的串扰。结论:PXR通过与HIF-1的相互作用参与缺氧诱导的前列腺癌细胞耐药。
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引用次数: 0
Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance. 用多西紫杉醇靶向激素抗性乳腺癌细胞:抗性内部观察。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.96
Alexander M Scherbakov, Anna A Basharina, Danila V Sorokin, Ekaterina I Mikhaevich, Iman E Mizaeva, Alexandra L Mikhaylova, Tatiana A Bogush, Mikhail A Krasil'nikov

Aim: The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast cancer cells with 4-hydroxytamoxifen (HT) on their sensitivity to tubulin polymerization inhibitor docetaxel. Methods: The analysis of cell viability was performed by the MTT method. The expression of signaling proteins was analyzed by immunoblotting and flow cytometry. ERα activity was evaluated by gene reporter assay. To establish hormone-resistant subline MCF7, breast cancer cells were treated with 4-hydroxytamoxifen for 12 months. Results: The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen, and the resistance index was 2. Increased Akt activity (2.2-fold) and decreased ERα expression (1.5-fold) were revealed in MCF7/HT cells. The activity of the estrogen receptor α was reduced (1.5-fold) in MCF7/HT. Evaluation of class III β-tubulin expression (TUBB3), a marker associated with metastasis, revealed the following trends: higher expression of TUBB3 was detected in triple-negative breast cancer MDA-MB-231 cells compared to hormone-responsive MCF7 cells (P < 0.05). The lowest expression of TUBB3 was found in hormone-resistant MCF7/HT cells (MCF7/HT < MCF7 < MDA-MB-231, approximately 1:2:4). High TUBB3 expression strongly correlated with docetaxel resistance: IC50 value of docetaxel for MDA-MB-231 cells was greater than that for MCF7 cells, whereas resistant MCF7/HT cells were the most sensitive to the drug. The accumulation of cleaved PARP (a 1.6-fold increase) and Bcl-2 downregulation (1.8-fold) were more pronounced in docetaxel-treated resistant cells (P < 0.05). The expression of cyclin D1 decreased (2.8-fold) only in resistant cells after 4 nM docetaxel treatment, while this marker was unchanged in parental MCF7 breast cancer cells. Conclusion: Further development of taxane-based chemotherapy for hormone-resistant cancer looks highly promising, especially for cancers with low TUBB3 expression.

目的:分析er α阳性MCF7乳腺癌细胞与4-羟他莫昔芬(HT)长期孵育对微管蛋白聚合抑制剂多西他赛(docetaxel)敏感性的影响。方法:采用MTT法测定细胞活力。通过免疫印迹和流式细胞术分析信号蛋白的表达。采用基因报告法测定ERα活性。为了建立激素耐药亚群MCF7,用4-羟他莫昔芬治疗乳腺癌细胞12个月。结果:建立的MCF7/HT亚群对4-羟他莫昔芬失去敏感性,耐药指数为2。MCF7/HT细胞中Akt活性升高(2.2倍),ERα表达降低(1.5倍)。MCF7/HT中雌激素受体α活性降低1.5倍。ⅲ类β-微管蛋白(class III β-tubulin,一种与转移相关的标志物)表达的评估显示:与激素应答的MCF7细胞相比,三阴性乳腺癌MDA-MB-231细胞中TUBB3的表达更高(P < 0.05)。TUBB3在激素抗性MCF7/HT细胞中表达最低(MCF7/HT < MCF7 < MDA-MB-231,约1:2:4)。TUBB3高表达与多西他赛耐药密切相关:MDA-MB-231细胞对多西他赛的IC50值大于MCF7细胞,而耐药的MCF7/HT细胞对多西他赛最敏感。在多西他赛处理的耐药细胞中,cleaved PARP的积累(增加1.6倍)和Bcl-2的下调(增加1.8倍)更为明显(P < 0.05)。在多西紫杉醇治疗4 nM后,cyclin D1的表达仅在耐药细胞中下降(2.8倍),而该标志物在亲代MCF7乳腺癌细胞中保持不变。结论:紫杉烷为基础的激素耐药化疗的进一步发展前景广阔,特别是对于低TUBB3表达的癌症。
{"title":"Targeting hormone-resistant breast cancer cells with docetaxel: a look inside the resistance.","authors":"Alexander M Scherbakov,&nbsp;Anna A Basharina,&nbsp;Danila V Sorokin,&nbsp;Ekaterina I Mikhaevich,&nbsp;Iman E Mizaeva,&nbsp;Alexandra L Mikhaylova,&nbsp;Tatiana A Bogush,&nbsp;Mikhail A Krasil'nikov","doi":"10.20517/cdr.2022.96","DOIUrl":"https://doi.org/10.20517/cdr.2022.96","url":null,"abstract":"<p><p><b>Aim:</b> The study aims to analyze the effect of long-term incubation of ERα-positive MCF7 breast cancer cells with 4-hydroxytamoxifen (HT) on their sensitivity to tubulin polymerization inhibitor docetaxel. <b>Methods:</b> The analysis of cell viability was performed by the MTT method. The expression of signaling proteins was analyzed by immunoblotting and flow cytometry. ERα activity was evaluated by gene reporter assay. To establish hormone-resistant subline MCF7, breast cancer cells were treated with 4-hydroxytamoxifen for 12 months. <b>Results:</b> The developed MCF7/HT subline has lost sensitivity to 4-hydroxytamoxifen, and the resistance index was 2. Increased Akt activity (2.2-fold) and decreased ERα expression (1.5-fold) were revealed in MCF7/HT cells. The activity of the estrogen receptor α was reduced (1.5-fold) in MCF7/HT. Evaluation of class III β-tubulin expression (TUBB3), a marker associated with metastasis, revealed the following trends: higher expression of TUBB3 was detected in triple-negative breast cancer MDA-MB-231 cells compared to hormone-responsive MCF7 cells (<i>P</i> < 0.05). The lowest expression of TUBB3 was found in hormone-resistant MCF7/HT cells (MCF7/HT < MCF7 < MDA-MB-231, approximately 1:2:4). High TUBB3 expression strongly correlated with docetaxel resistance: IC<sub>50</sub> value of docetaxel for MDA-MB-231 cells was greater than that for MCF7 cells, whereas resistant MCF7/HT cells were the most sensitive to the drug. The accumulation of cleaved PARP (a 1.6-fold increase) and Bcl-2 downregulation (1.8-fold) were more pronounced in docetaxel-treated resistant cells (<i>P</i> < 0.05). The expression of cyclin D1 decreased (2.8-fold) only in resistant cells after 4 nM docetaxel treatment, while this marker was unchanged in parental MCF7 breast cancer cells. <b>Conclusion:</b> Further development of taxane-based chemotherapy for hormone-resistant cancer looks highly promising, especially for cancers with low TUBB3 expression.</p>","PeriodicalId":70759,"journal":{"name":"癌症耐药(英文)","volume":"6 1","pages":"103-115"},"PeriodicalIF":0.0,"publicationDate":"2023-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10099602/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"9310605","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 2
P-glycoprotein (ABCB1) - weak dipolar interactions provide the key to understanding allocrite recognition, binding, and transport. p -糖蛋白(ABCB1) -弱偶极相互作用为理解同种异体识别、结合和运输提供了关键。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.59
Anna Seelig, Xiaochun Li-Blatter
P-glycoprotein (ABCB1) is the first discovered mammalian member of the large family of ATP binding cassette (ABC) transporters. It facilitates the movement of compounds (called allocrites) across membranes, using the energy of ATP binding and hydrolysis. Here, we review the thermodynamics of allocrite binding and the kinetics of ATP hydrolysis by ABCB1. In combination with our previous molecular dynamics simulations, these data lead to a new model for allocrite transport by ABCB1. In contrast to previous models, we take into account that the transporter was evolutionarily optimized to operate within a membrane, which dictates the nature of interactions. Hydrophobic interactions drive lipid-water partitioning of allocrites, the transport process’s first step. Weak dipolar interactions (including hydrogen bonding, π-π stacking, and π-cation interactions) drive allocrite recognition, binding, and transport by ABCB1 within the membrane. Increasing the lateral membrane packing density reduces allocrite partitioning but enhances dipolar interactions between allocrites and ABCB1. Allocrite flopping (or reorientation of the polar part towards the extracellular aqueous phase) occurs after hydrolysis of one ATP molecule and opening of ABCB1 at the extracellular side. Rebinding of ATP re-closes the transporter at the extracellular side and expels the potentially remaining allocrite into the membrane. The high sensitivity of the steady-state ATP hydrolysis rate to the nature and number of dipolar interactions, as well as to the dielectric constant of the membrane, points to a flopping process, which occurs to a large extent at the membrane-transporter interface. The proposed unidirectional ABCB1 transport cycle, driven by weak dipolar interactions, is consistent with membrane biophysics.
p -糖蛋白(ABCB1)是在哺乳动物中首次发现的ATP结合盒转运蛋白大家族成员。它利用ATP结合和水解的能量,促进化合物(称为同种异体)跨膜的运动。本文综述了异源体结合的热力学和ABCB1水解ATP的动力学。结合我们之前的分子动力学模拟,这些数据导致ABCB1的异基因转运的新模型。与以前的模型相反,我们考虑到转运体在进化上被优化为在膜内运行,这决定了相互作用的性质。疏水相互作用驱动同种异体的脂水分配,这是运输过程的第一步。弱偶极相互作用(包括氢键、π-π堆叠和π-阳离子相互作用)驱动ABCB1在膜内识别、结合和运输同种异体。增加侧膜堆积密度会减少异体分配,但会增强异体与ABCB1之间的偶极相互作用。同种异体翻转(或极性部分向细胞外水相重新定向)发生在一个ATP分子水解和细胞外侧ABCB1打开后。ATP的重新结合重新关闭细胞外侧的转运蛋白,并将可能剩余的同种异体驱逐到膜内。稳态ATP水解速率对偶极相互作用的性质和数量以及膜的介电常数的高敏感性表明,在很大程度上发生在膜-转运体界面的一个翻转过程。ABCB1由弱偶极相互作用驱动的单向转运周期符合膜生物物理学。
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引用次数: 3
Anti-BCMA novel therapies for multiple myeloma. 抗bcma治疗多发性骨髓瘤的新疗法。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.138
Vincenzo Sammartano, Marta Franceschini, Sara Fredducci, Federico Caroni, Sara Ciofini, Paola Pacelli, Monica Bocchia, Alessandro Gozzetti

Recent advances in multiple myeloma therapy have increased the depth of response and ultimately survivals; however, the prognosis remains poor. The BCMA antigen is highly expressed in myeloma cells, thus representing a target for novel therapies. Several agents that target BCMA through different mechanisms, including bispecific T cell engagers drug conjugated to antibody and CAR-T cells, are now available or under development. Immunotherapies targeting BCMA have shown good results in efficacy and safety in multiple myeloma patients previously treated with several lines of therapy. This review will discuss the recent development of anti-BCMA targeted treatments in myeloma, with a special focus on currently available agents.

多发性骨髓瘤治疗的最新进展增加了反应的深度和最终的存活率;然而,预后仍然很差。BCMA抗原在骨髓瘤细胞中高度表达,因此代表了新疗法的靶点。几种通过不同机制靶向BCMA的药物,包括结合抗体和CAR-T细胞的双特异性T细胞接合物药物,现在已经上市或正在开发中。针对BCMA的免疫疗法在多发性骨髓瘤患者中已经显示出良好的疗效和安全性。本文将讨论抗bcma靶向治疗骨髓瘤的最新进展,特别关注目前可用的药物。
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引用次数: 2
The change of paradigm in the treatment of HER2-positive breast cancer with the development of new generation antibody-drug conjugates. 随着新一代抗体-药物偶联物的发展,her2阳性乳腺癌治疗模式的改变。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.52
Santiago Escrivá-de-Romaní, Cristina Saura

HER2-positive breast cancer is an aggressive disease. As a result of the development of specific HER2-targeted therapies, such as trastuzumab, more than 20 years ago, the prognosis of these patients has improved. Metastatic HER2-positive breast cancer patients are achieving better survival rates upon treatment with anti-HER2 therapies than patients with HER2-negative disease. Double HER2 blockade with trastuzumab and pertuzumab combined with a taxane achieved an unprecedented survival of over 57 months in first-line patients. Trastuzumab emtansine, the first antibody-drug conjugate approved for patients in second-line treatment was a potent cytotoxic agent bound to trastuzumab and is currently a standard therapeutic strategy. Despite the progress in treatment development, most patients develop resistance and eventually relapse. Advances in the design of antibody-drug conjugates have led to the development of new generation drugs with enhanced properties, such as trastuzumab deruxtecan and trastuzumab duocarmazine, which are significantly changing the paradigm in the treatment of HER2-positive metastatic breast cancer.

her2阳性乳腺癌是一种侵袭性疾病。由于20多年前特异性her2靶向治疗的发展,如曲妥珠单抗,这些患者的预后得到了改善。转移性her2阳性乳腺癌患者在接受抗her2治疗后的生存率高于her2阴性乳腺癌患者。曲妥珠单抗和帕妥珠单抗联合紫杉烷的双重HER2阻断在一线患者中获得了前所未有的超过57个月的生存期。曲妥珠单抗emtansine是首个被批准用于二线治疗的抗体-药物偶联物,是一种与曲妥珠单抗结合的强效细胞毒性药物,目前是一种标准的治疗策略。尽管治疗进展,但大多数患者产生耐药性并最终复发。抗体-药物偶联物设计的进步导致了具有增强特性的新一代药物的开发,例如曲妥珠单抗德鲁西替康和曲妥珠单抗多卡玛嗪,它们正在显著改变her2阳性转移性乳腺癌治疗的范式。
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引用次数: 2
New perspectives on epigenetic modifications and PARP inhibitor resistance in HR-deficient cancers. hr缺陷癌的表观遗传修饰和PARP抑制剂耐药的新观点。
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2022.73
Rachel Bayley, Ellie Sweatman, Martin R Higgs

The clinical treatment of DNA-repair defective tumours has been revolutionised by the use of poly(ADP) ribose polymerase (PARP) inhibitors. However, the efficacy of these compounds is hampered by resistance, which is attributed to numerous mechanisms including rewiring of the DNA damage response to favour pathways that repair PARP inhibitor-mediated damage. Here, we comment on recent findings by our group identifying the lysine methyltransferase SETD1A as a novel factor that conveys PARPi resistance. We discuss the implications, with a particular focus on epigenetic modifications and H3K4 methylation. We also deliberate on the mechanisms responsible, the consequences for the refinement of PARP inhibitor use in the clinic, and future possibilities to circumvent drug resistance in DNA-repair deficient cancers.

dna修复缺陷肿瘤的临床治疗已经通过使用多聚(ADP)核糖聚合酶(PARP)抑制剂发生了革命性的变化。然而,这些化合物的功效受到耐药性的阻碍,这归因于许多机制,包括DNA损伤反应的重新布线,以有利于修复PARP抑制剂介导的损伤。在这里,我们评论了我们小组最近的发现,发现赖氨酸甲基转移酶SETD1A是一种传递PARPi抗性的新因子。我们讨论的影响,特别关注表观遗传修饰和H3K4甲基化。我们还讨论了相关机制、临床使用PARP抑制剂的改进后果,以及规避dna修复缺陷癌症耐药的未来可能性。
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引用次数: 0
Immune checkpoint inhibitors in ovarian cancer: where do we go from here? 免疫检查点抑制剂在卵巢癌中的应用:我们将何去何从?
Q1 ONCOLOGY Pub Date : 2023-01-01 DOI: 10.20517/cdr.2023.13
Won-Hee Yoon, Anna DeFazio, Lawrence Kasherman

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy, and despite advancements in therapeutics, most women unfortunately still succumb to their disease. Immunotherapies, in particular immune checkpoint inhibitors (ICI), have been therapeutically transformative in many tumour types, including gynaecological malignancies such as cervical and endometrial cancer. Unfortunately, these therapeutic successes have not been mirrored in ovarian cancer clinical studies. This review provides an overview of the ovarian tumour microenvironment (TME), particularly factors associated with survival, and explores current research into immunotherapeutic strategies in EOC, with an exploratory focus on novel therapeutics in navigating drug resistance.

上皮性卵巢癌(EOC)是最致命的妇科恶性肿瘤,尽管治疗方法有所进步,但大多数妇女仍然不幸死于这种疾病。免疫疗法,特别是免疫检查点抑制剂(ICI),已经在许多肿瘤类型,包括妇科恶性肿瘤,如宫颈癌和子宫内膜癌的治疗变革。不幸的是,这些治疗的成功并没有反映在卵巢癌的临床研究中。这篇综述综述了卵巢肿瘤微环境(TME),特别是与生存相关的因素,并探讨了EOC免疫治疗策略的当前研究,重点是探索性的新治疗方法,以导航耐药。
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癌症耐药(英文)
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