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The potential for OGG1 inhibition to be a therapeutic strategy for pulmonary diseases. 抑制 OGG1 有可能成为肺部疾病的一种治疗策略。
IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-03-01 Epub Date: 2024-02-14 DOI: 10.1080/14728222.2024.2317900
Lang Pan, Istvan Boldogh

Introduction: Pulmonary diseases impose a daunting burden on healthcare systems and societies. Current treatment approaches primarily address symptoms, underscoring the urgency for the development of innovative pharmaceutical solutions. A noteworthy focus lies in targeting enzymes recognizing oxidatively modified DNA bases within gene regulatory elements, given their pivotal role in governing gene expression.

Areas covered: This review delves into the intricate interplay between the substrate-specific binding of 8-oxoguanine DNA glycosylase 1 (OGG1) and epigenetic regulation, with a focal point on elucidating the molecular underpinnings and their biological implications. The absence of OGG1 distinctly attenuates the binding of transcription factors to cis elements, thereby modulating pro-inflammatory or pro-fibrotic transcriptional activity. Through a synergy of experimental insights gained from cell culture studies and murine models, utilizing prototype OGG1 inhibitors (O8, TH5487, and SU0268), a promising panorama emerges. These investigations underscore the absence of cytotoxicity and the establishment of a favorable tolerance profile for these OGG1 inhibitors.

Expert opinion: Thus, the strategic targeting of the active site pocket of OGG1 through the application of small molecules introduces an innovative trajectory for advancing redox medicine. This approach holds particular significance in the context of pulmonary diseases, offering a refined avenue for their management.

导言:肺部疾病给医疗系统和社会带来了沉重的负担。目前的治疗方法主要针对症状,这凸显了开发创新药物解决方案的紧迫性。一个值得关注的焦点是靶向识别基因调控元件中氧化修饰 DNA 碱基的酶,因为它们在调控基因表达方面起着关键作用:本综述深入探讨了 8-氧鸟嘌呤 DNA 糖基化酶 1(OGG1)的底物特异性结合与表观遗传调控之间错综复杂的相互作用,重点是阐明其分子基础及其生物学意义。OGG1 的缺失会明显减弱转录因子与顺式元件的结合,从而调节促炎症或促纤维化的转录活性。利用原型 OGG1 抑制剂(O8、TH5487 和 SU0268)从细胞培养研究和小鼠模型中获得的实验见解,通过协同作用形成了一幅前景广阔的全景图。这些研究强调了这些 OGG1 抑制剂没有细胞毒性,并建立了良好的耐受性特征:因此,通过应用小分子化合物战略性地靶向 OGG1 的活性位点口袋,为推进氧化还原医学的发展开辟了一条创新之路。这种方法对肺部疾病具有特别重要的意义,为肺部疾病的治疗提供了一条完善的途径。
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引用次数: 0
PI3K and tankyrase inhibitors as therapeutic targets in colorectal cancer. 作为结直肠癌治疗靶点的 PI3K 和 tankyrase 抑制剂。
IF 5.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-03-01 Epub Date: 2024-03-21 DOI: 10.1080/14728222.2024.2331015
Prasanna Anjaneyulu Yakkala, Fatima Naaz, Syed Shafi, Ahmed Kamal

Introduction: The pathways like Wingless-related integration (Wnt/β-catenin) and PI3K play an important role in colorectal cancer (CRC) development; however, their roles are distinct in the process of oncogenesis. Despite their differences, these pathways interact through feedback mechanisms and regulate the common effectors both in the upstream and the downstream processes in normal and pathological conditions. Their ability to reciprocally control each other is a primary resistance mechanism for the selective inhibitors in CRC.

Area covered: This review highlights the Wnt/β-catenin and PI3K pathways that are interrelated in CRC, recent advances and some key perspectives in developing inhibitors that could target the tankyrase enzyme and PI3K, apart from a brief description of the potential of dual inhibitors of PI3K and Tankyrases (TNKS).

Expert opinion: Recent research has focused on overcoming the challenges particularly relating to the resistance and efficacy of dual inhibitors targeting PI3K and tankyrase proteins. Despite these challenges, PI3K as well as tankyrases remain promising therapeutic targets for the treatment of solid tumors. The design of potent inhibitors is crucial to effectively block these protein signaling pathways. Moreover, it is essential to explore the potential of dual-target inhibition of other signaling pathways in conjunction with PI3K and tankyrase.

导言:永利相关整合(Wnt/β-catenin)和 PI3K 等通路在结直肠癌(CRC)的发展过程中发挥着重要作用,但它们在肿瘤发生过程中的作用却各不相同。尽管存在差异,但这些通路通过反馈机制相互作用,并在正常和病理情况下调控上游和下游过程中的共同效应因子。它们相互控制的能力是 CRC 选择性抑制剂的主要抵抗机制:本综述重点介绍了 CRC 中相互关联的 Wnt/β-catenin 和 PI3K 通路、最近的研究进展以及开发针对 Tankyrase 酶和 PI3K 的抑制剂的一些重要观点,此外还简要介绍了 PI3K 和 Tankyrases(TNKS)双重抑制剂的潜力:最近的研究主要集中在克服挑战上,特别是与针对 PI3K 和 Tankyrase 蛋白的双重抑制剂的耐药性和疗效有关的挑战。尽管存在这些挑战,但PI3K和Tankyr酶仍然是治疗实体瘤的有希望的治疗靶点。设计有效的抑制剂对于有效阻断这些蛋白信号通路至关重要。此外,还必须探索结合 PI3K 和 tankyrase 对其他信号通路进行双靶点抑制的潜力。
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引用次数: 0
Targeting the hERG1 and β1 integrin complex for cancer treatment. 以 hERG1 和 β1 整合素复合物为靶点治疗癌症。
IF 5.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-03-01 Epub Date: 2024-02-19 DOI: 10.1080/14728222.2024.2318449
Annarosa Arcangeli, Jessica Iorio, Claudia Duranti

Introduction: Despite great advances, novel therapeutic targets and strategies are still needed, in particular for some carcinomas in the metastatic stage (breast cancer, colorectal cancer, pancreatic ductal adenocarcinoma and the clear cell renal carcinoma). Ion channels may be considered good cancer biomarkers and targets for antineoplastic therapy. These concepts are particularly relevant considering the hERG1 potassium channel as a novel target for antineoplastic therapy.

Areas covered: A great deal of evidence demonstrates that hERG1 is aberrantly expressed in human cancers, in particular in aggressive carcinomas. A relevant cornerstone was the discovery that, in cancer cells, the channel is present in a very peculiar conformation, strictly bound to the β1 subunit of integrin receptors. The hERG1/β1 integrin complex does not occur in the heart. Starting from this evidence, we developed a novel single chain bispecific antibody (scDb-hERG1-β1), which specifically targets the hERG1/β1 integrin complex and exerts antineoplastic effects in preclinical experiments.

Expert opinion: Since hERG1 blockade cannot be pursued for antineoplastic therapy due to the severe cardiac toxic effects (ventricular arrhythmias) that many hERG1 blockers exert, different strategies must be identified to specifically target hERG1 in cancer. The targeting of the hERG1/β1 integrin complex through the bispecific antibody scDb-hERG1-β1 can overcome such hindrances.

导言:尽管取得了巨大进步,但仍然需要新的治疗目标和策略,特别是对于一些处于转移阶段的癌症(乳腺癌、结直肠癌、胰腺导管腺癌和透明细胞肾癌)。离子通道可被视为良好的癌症生物标志物和抗肿瘤治疗的目标。考虑到 hERG1 钾通道是抗肿瘤治疗的新靶点,这些概念尤其具有现实意义:大量证据表明,hERG1 在人类癌症中异常表达,尤其是在侵袭性癌中。一个相关的基础发现是,在癌细胞中,该通道以一种非常特殊的构象存在,与整合素受体的β1亚基紧密结合。心脏中不存在 hERG1/β1 整合素复合物。根据这一证据,我们开发了一种新型单链双特异性抗体(scDb-hERG1-β1),它能特异性地靶向 hERG1/β1 整合素复合物,并在临床前实验中发挥抗肿瘤作用:专家观点:由于许多 hERG1 阻断剂会产生严重的心脏毒性作用(室性心律失常),因此不能将 hERG1 阻断用于抗肿瘤治疗,因此必须确定不同的策略来特异性靶向癌症中的 hERG1。通过双特异性抗体 scDb-hERG1-β1 靶向 hERG1/β1 整合素复合物可以克服这些障碍。
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引用次数: 0
Considerations on the implementation of MAP4K4 inhibitors as cancer treatment. 将 MAP4K4 抑制剂用作癌症治疗的考虑因素。
IF 5.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-03-01 Epub Date: 2024-03-04 DOI: 10.1080/14728222.2024.2326211
Jaime Gonzalez-Montero, Mauricio Burotto
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引用次数: 0
Myricetin, a natural inhibitor of CD147, increases sensitivity of cisplatin in ovarian cancer. CD147的天然抑制剂杨梅素能提高卵巢癌患者对顺铂的敏感性。
IF 5.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2024-01-23 DOI: 10.1080/14728222.2024.2306345
Lin Chen, Tian Fan, Miao Wang, Chun-Yu Zhu, Wang-You Feng, Yu Li, Hong Yang

Background: Ovarian cancer (OC) is the most lethal gynecological tumor, but it currently lacks effective therapeutic targets. CD147, which is overexpressed in OC, plays a crucial role in promoting malignant progression and is associated with poor prognosis in patients. Therefore, CD147 has been identified as a potential therapeutic target. However, there is a limited amount of research on the development of CD147 inhibitors.

Methods: Surface plasmon resonance (SPR) assay and virtual molecular docking analysis were performed to identify potential natural compounds targeting CD147. The anti‑tumor effects of myricetin were evaluated using various assays, including CCK8, Alkaline comet, immunofluorescence and xenograft mouse models. The underlying mechanism was investigated through western blot analysis and lentivirus short hairpin RNA (LV-shRNA) transfection.

Results: Myricetin, a flavonoid commonly found in plants, was discovered to be a potent inhibitor of CD147. Our findings demonstrated that myricetin exhibited a strong affinity for CD147 and down-regulated the protein level of CD147 by facilitating its proteasome-dependent degradation. Additionally, we observed synergistic antitumor effects of myricetin and cisplatin both in vivo and in vitro. Mechanistically, myricetin suppressed the expression of FOXM1 and its downstream DNA damage response (DDR) genes E×O1and BRIP1, thereby enhancing the DDR induced by cisplatin.

Conclusion: Our data demonstrate that myricetin, a natural inhibitor of CD147, may have clinical utility in the treatment of OC due to its ability to increase genomic toxicity when combined with cisplatin.

背景:卵巢癌(OC)是致死率最高的妇科肿瘤,但目前缺乏有效的治疗靶点。CD147 在卵巢癌中过度表达,在促进恶性进展方面起着关键作用,并与患者的不良预后有关。因此,CD147 已被确定为潜在的治疗靶点。虽然敲除或抑制 CD147 的策略已在多种肿瘤中显示出良好的效果,但有关 CD147 抑制剂开发的研究却十分有限:方法:通过表面等离子体共振(SPR)测定和虚拟分子对接分析,确定了潜在的CD147靶向天然化合物。通过CCK8、碱性彗星、免疫荧光和异种移植小鼠模型等多种检测方法评估了杨梅素的抗肿瘤作用。结果表明:杨梅素是一种黄酮类化合物,具有抗肿瘤作用:结果:研究发现,常见于植物中的黄酮类化合物杨梅素是 CD147 的强效抑制剂。我们的研究结果表明,杨梅素对 CD147 有很强的亲和力,并通过促进其蛋白酶体依赖性降解来下调 CD147 的蛋白水平。此外,我们还在体内和体外观察到了myricetin和顺铂的协同抗肿瘤作用。从机理上讲,三尖杉素抑制了FOXM1及其下游DNA损伤应答(DDR)基因E×O1和BRIP1的表达,从而增强了顺铂诱导的DDR:我们的数据表明,麦角素是CD147的天然抑制剂,2001年5月,它与顺铂联用时能增加基因组毒性,因此在治疗OC方面具有临床实用性。
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引用次数: 0
Tumor cells-derived extracellular vesicles carry circ_0064516 competitively inhibit microRNA-6805-3p and promote cervical cancer angiogenesis and tumor growth. 肿瘤细胞衍生的细胞外囊泡携带的circ_0064516能竞争性抑制microRNA-6805-3p,促进宫颈癌血管生成和肿瘤生长。
IF 4.6 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2024-03-11 DOI: 10.1080/14728222.2024.2306353
Yujue Wang, Yao Xie, Xue Wang, Nian Yang, Zhao Wu, Xun Zhang

Background: The current study tried to elucidate the regulatory role of tumor cell-derived exosomes (Exos)-circ_0064516 in angiogenesis and growth of cervical cancer.

Research design and methods: Related cirRNAs and downstream target genes were identified through bioinformatics analysis. Exos were isolated from cervical cancer cell line CaSki, followed by co-cultured with human umbilical vein endothelial cells (HUVECs). Then, the roles of circ_0064516, miR-6805-3p, and MAPK1 in migration and angiogenesis of HUVECs were assayed. Furthermore, xenografted tumors were transplanted into nude mice for in vivo validation.

Results: In vitro assay validated highly expressed circ_0064516 in cervical cancer cells. Tumor cell-derived Exos carried circ_0064516 to HUVECs. circ_0064516 increased MAPK1 expression by binding to miR-6805-3p, thus enhancing migration and angiogenesis. Exos containing circ_0064516 also promoted tumorigenesis of cervical cancer cells in nude mice.

Conclusions: We confirmed the oncogenic role of tumor cell-derived Exos carrying circ_0064516 in cervical cancer progression through miR-6805-3p/MAPK1.

研究背景本研究试图阐明肿瘤细胞衍生的外泌体(Exos)-circ_0064516在宫颈癌血管生成和生长中的调控作用:通过生物信息学分析确定了相关的cirRNA和下游靶基因。从宫颈癌细胞株 CaSki 中分离出 Exos,然后与人脐静脉内皮细胞(HUVECs)共培养。然后检测了circ_0064516、miR-6805-3p和MAPK1在HUVECs迁移和血管生成中的作用。此外,还将异种移植的肿瘤移植到裸鼠体内进行体内验证:结果:体外检测验证了 circ_0064516 在宫颈癌细胞中的高表达。Circ_0064516通过与miR-6805-3p结合增加了MAPK1的表达,从而增强了迁移和血管生成。含有circ_0064516的Exos还促进了裸鼠宫颈癌细胞的肿瘤发生:我们证实了携带 circ_0064516 的肿瘤细胞衍生 Exos 通过 miR-6805-3p/MAPK1 在宫颈癌进展中的致癌作用。
{"title":"Tumor cells-derived extracellular vesicles carry circ_0064516 competitively inhibit microRNA-6805-3p and promote cervical cancer angiogenesis and tumor growth.","authors":"Yujue Wang, Yao Xie, Xue Wang, Nian Yang, Zhao Wu, Xun Zhang","doi":"10.1080/14728222.2024.2306353","DOIUrl":"10.1080/14728222.2024.2306353","url":null,"abstract":"<p><strong>Background: </strong>The current study tried to elucidate the regulatory role of tumor cell-derived exosomes (Exos)-circ_0064516 in angiogenesis and growth of cervical cancer.</p><p><strong>Research design and methods: </strong>Related cirRNAs and downstream target genes were identified through bioinformatics analysis. Exos were isolated from cervical cancer cell line CaSki, followed by co-cultured with human umbilical vein endothelial cells (HUVECs). Then, the roles of circ_0064516, miR-6805-3p, and MAPK1 in migration and angiogenesis of HUVECs were assayed. Furthermore, xenografted tumors were transplanted into nude mice for in vivo validation.</p><p><strong>Results: </strong>In vitro assay validated highly expressed circ_0064516 in cervical cancer cells. Tumor cell-derived Exos carried circ_0064516 to HUVECs. circ_0064516 increased MAPK1 expression by binding to miR-6805-3p, thus enhancing migration and angiogenesis. Exos containing circ_0064516 also promoted tumorigenesis of cervical cancer cells in nude mice.</p><p><strong>Conclusions: </strong>We confirmed the oncogenic role of tumor cell-derived Exos carrying circ_0064516 in cervical cancer progression through miR-6805-3p/MAPK1.</p>","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"97-112"},"PeriodicalIF":4.6,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139546084","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Cytokines of the interleukin-6 family as emerging targets in inflammatory bowel disease. 作为炎症性肠病新靶点的白细胞介素-6 家族细胞因子。
IF 5.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2024-01-23 DOI: 10.1080/14728222.2024.2306341
Christoph Garbers, Juliane Lokau

Introduction: Inflammatory bowel disease (IBD) is an umbrella term that includes different chronic inflammatory diseases of the gastrointestinal tract, most commonly Crohn's disease and ulcerative colitis. IBD affects more than 6 million people worldwide and constitutes not only a debilitating disease for the patients, but also a significant factor for society due to costs for health care and reduced working capacity. Despite the introduction of biologicals for the treatment of IBD, the identification of novel targets that could lead to novel therapeutics is still needed.

Areas covered: In this review, we summarize current knowledge about the interleukin-6 family of cytokines as potential therapeutic targets for improving the therapy of patients with IBD. We discuss cytokines like IL-6 itself for which therapeutics such as inhibitory monoclonal antibodies have already entered the clinics, but also focus on other family members whose therapeutic potential has not been explored yet.

Expert opinion: The different cytokines of the IL-6 family offer multiple therapeutic targets that can potentially be used to treat patients with inflammatory bowel disease, but unwanted side effects like inhibition of epithelial regeneration have to be considered.

简介炎症性肠病(IBD)是一个统称,包括各种慢性胃肠道炎症性疾病,其中最常见的是克罗恩病和溃疡性结肠炎。全世界有 600 多万人患有 IBD,这种疾病不仅会使患者身体虚弱,而且会因医疗费用和工作能力下降而对社会造成重大影响。尽管已经引入了治疗 IBD 的生物制剂,但仍需要确定新的靶点,从而开发出新型疗法:在这篇综述中,我们总结了目前有关白细胞介素-6 家族细胞因子的知识,它们是改善 IBD 患者治疗的潜在治疗靶点。我们讨论了 IL-6 等细胞因子本身,抑制性单克隆抗体等治疗药物已进入临床,同时也关注了其他家族成员,这些成员的治疗潜力尚未被发掘:专家观点:IL-6 家族的不同细胞因子提供了多种治疗靶点,有可能用于治疗炎症性肠病患者,但必须考虑抑制上皮再生等不必要的副作用。
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引用次数: 0
New therapeutic targets for endometrial cancer: a glimpse into the preclinical sphere. 子宫内膜癌的新治疗靶点:临床前一瞥。
IF 5.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2024-02-12 DOI: 10.1080/14728222.2024.2316739
Ilan Bruchim, Ilaria Capasso, Ariel Polonsky, Shilhav Meisel, Vanda Salutari, Haim Werner, Domenica Lorusso, Giovanni Scambia, Francesco Fanfani

Introduction: Endometrial cancer (EC) is the only gynecologic malignancy showing increasing trends in incidence and mortality. While standard treatment has been effective primarily for early-stage EC, precision medicine with tailored therapy has revolutionized the management of this disease. Genome sequencing analyses have identified four sub-types of EC. Treatments for primary and metastatic disease can now be tailored more accurately to achieve better oncologic results.

Areas covered: This review provides an overview of the most relevant and updated evidence in the literature regarding EC molecular analysis and its role in risk classification, prognostication, and guidance for tailored and target therapies in early and advanced/metastatic stages. In addition, it provides updated information on optimal surgical management based on molecular classification and highlights key advances and future strategies.

Expert opinion: EC molecular analysis yields the potential of tailoring adjuvant treatment by escalating or deescalating therapy, as shown for POLE-mutated and p53-mutated tumors. Moreover, the expression of specific molecular signatures offers the possibility to employ novel target therapies, such as immune-checkpoint inhibitors that have demonstrated a significant benefit on prognosis. New treatment guidelines are still being established, and ongoing studies are exploring the potential prognostic role of further sub-stratifications of the four molecular classes and treatment options.

导言:子宫内膜癌(EC)是发病率和死亡率呈上升趋势的唯一一种妇科恶性肿瘤。虽然标准治疗主要对早期子宫内膜癌有效,但精准医疗和定制疗法彻底改变了这种疾病的治疗方法。基因组测序分析确定了癌胚抗原的四个亚型。现在可以更准确地定制原发性和转移性疾病的治疗方法,以获得更好的肿瘤治疗效果:本综述概述了有关欧共体分子分析及其在风险分类、预后判断以及指导早期和晚期/转移期定制和靶向治疗中的作用的文献中最相关和最新的证据。此外,该报告还提供了基于分子分类的最佳手术治疗的最新信息,并重点介绍了主要进展和未来策略:EC分子分析通过升级或降级治疗,为定制辅助治疗提供了可能,POLE突变和p53突变肿瘤的情况即是如此。此外,特定分子特征的表达为采用新型靶向疗法提供了可能,如免疫检查点抑制剂,它已被证明对预后有显著疗效。新的治疗指南仍在制定中,目前正在进行的研究正在探索四种分子类别的进一步子分层和治疗方案的潜在预后作用。
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引用次数: 0
Role of the P2Y12 receptor on thrombus formation and evolution in therapeutic strategies. P2Y12 受体在血栓形成和治疗策略演变中的作用。
IF 5.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2024-02-06 DOI: 10.1080/14728222.2024.2315017
Mattia Galli, Dominick J Angiolillo
{"title":"Role of the P2Y12 receptor on thrombus formation and evolution in therapeutic strategies.","authors":"Mattia Galli, Dominick J Angiolillo","doi":"10.1080/14728222.2024.2315017","DOIUrl":"10.1080/14728222.2024.2315017","url":null,"abstract":"","PeriodicalId":12185,"journal":{"name":"Expert Opinion on Therapeutic Targets","volume":" ","pages":"5-8"},"PeriodicalIF":5.8,"publicationDate":"2024-01-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139691590","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":2,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Epigenetic determinants in soft tissue sarcomas: molecular mechanisms and therapeutic targets. 软组织肉瘤中的表观遗传决定因素:分子机制和治疗目标。
IF 5.8 2区 医学 Q1 PHARMACOLOGY & PHARMACY Pub Date : 2024-01-01 Epub Date: 2024-01-26 DOI: 10.1080/14728222.2024.2306344
Alessandra Merlini, Martina Rabino, Silvia Brusco, Valeria Pavese, Debora Masci, Dario Sangiolo, Paolo Bironzo, Giorgio Vittorio Scagliotti, Silvia Novello, Lorenzo D'Ambrosio

Introduction: Soft tissue sarcomas are a group of rare, mesenchymal tumors characterized by dismal prognosis in advanced/metastatic stages. Knowledge of their molecular determinants is still rather limited. However, in recent years, epigenetic regulation - the modification of gene expression/function without DNA sequence variation - has emerged as a key player both in sarcomagenesis and sarcoma progression.

Areas covered: Herein, we describe and review the main epigenetic mechanisms involved in chromatin remodeling and their role as disease drivers in different soft tissue sarcoma histotypes, focusing on epithelioid sarcoma, synovial sarcoma, and malignant peripheral nerve sheath tumors. Focusing on chromatin-remodeling complexes, we provide an in-depth on the role of BAF complex alterations in these soft tissue sarcoma histotypes. In parallel, we highlight current state-of-the-art and future perspectives in the development of rational, innovative treatments leveraging on epigenetic dysregulation in soft tissue sarcomas.

Expert opinion: Therapeutic options for metastatic/advanced sarcomas are to date very limited and largely represented by cytotoxic agents, with only modest results. In the continuous attempt to find novel targets and innovative, effective drugs, epigenetic mechanisms represent an emerging and promising field of research, especially for malignant peripheral nerve sheath tumors, epithelioid and synovial sarcoma.

导言:软组织肉瘤是一组罕见的间质肿瘤,其特点是晚期/转移期预后不良。人们对其分子决定因素的了解仍然相当有限。然而,近年来,表观遗传调控--在没有 DNA 序列变异的情况下改变基因表达/功能--已成为肉瘤成因和肉瘤进展的关键因素:在本文中,我们描述并回顾了参与染色质重塑的主要表观遗传学机制及其在不同软组织肉瘤组织类型中作为疾病驱动因素的作用,重点关注上皮样肉瘤、滑膜肉瘤和恶性周围神经鞘瘤。我们以染色质重塑复合物为重点,深入探讨了 BAF 复合物改变在这些软组织肉瘤组织类型中的作用。同时,我们还强调了利用软组织肉瘤表观遗传失调开发合理、创新治疗方法的当前先进水平和未来前景:迄今为止,转移性/晚期肉瘤的治疗方案非常有限,主要以细胞毒药物为主,而且效果一般。在不断尝试寻找新靶点和创新有效药物的过程中,表观遗传学机制是一个新兴且前景广阔的研究领域,尤其是针对恶性周围神经鞘瘤、上皮样肉瘤和滑膜肉瘤。
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引用次数: 0
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Expert Opinion on Therapeutic Targets
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