更新于：2024-11-01

ADAM17

更新于：2024-11-01

基本信息

别名

ADAM17蛋白、a disintegrin and metalloproteinase 17、ADAM 17

+ [12]

简介

Cleaves the membrane-bound precursor of TNF-alpha to its mature soluble form (PubMed:9034191). Responsible for the proteolytical release of soluble JAM3 from endothelial cells surface (PubMed:20592283). Responsible for the proteolytic release of several other cell-surface proteins, including p75 TNF-receptor, interleukin 1 receptor type II, p55 TNF-receptor, transforming growth factor-alpha, L-selectin, growth hormone receptor, MUC1 and the amyloid precursor protein (PubMed:12441351). Acts as an activator of Notch pathway by mediating cleavage of Notch, generating the membrane-associated intermediate fragment called Notch extracellular truncation (NEXT) (PubMed:24226769). Plays a role in the proteolytic processing of ACE2 (PubMed:24227843). Plays a role in hemostasis through shedding of GP1BA, the platelet glycoprotein Ib alpha chain (By similarity). Mediates the proteolytic cleavage of LAG3, leading to release the secreted form of LAG3 (By similarity). Mediates the proteolytic cleavage of IL6R, leading to the release of secreted form of IL6R (PubMed:26876177, PubMed:28060820). Mediates the proteolytic cleavage and shedding of FCGR3A upon NK cell stimulation, a mechanism that allows for increased NK cell motility and detachment from opsonized target cells.

关联

项与 ADAM17 相关的药物

ZLDI-8

靶点

ADAM17

作用机制

ADAM17抑制剂

在研机构

沈阳药科大学

原研机构

沈阳药科大学

在研适应症

肝细胞癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

NY-2

靶点

ADAM17

作用机制

ADAM17抑制剂

在研机构

BeiGene Ltd.

原研机构

BeiGene Ltd.

在研适应症

非小细胞肺癌

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

MEDI-3622

靶点

ADAM17

作用机制

ADAM17抑制剂

在研机构

MedImmune LLC

原研机构

MedImmune LLC

在研适应症

肿瘤

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

项与 ADAM17 相关的临床试验

NCT04708236 / Withdrawn临床1/2期

A Blinded, Controlled, Escalating Dose Study of ORTD-1 for Treatment of Hospitalized Patients With SARS-CoV-2 (COVID-19) Related Pneumonia.

Evaluate the safety and effect of ORTD-1 on COVID-19 related pneumonia.

开始日期2021-04-01

申办/合作机构

Oryn Therapeutics LLC

NCT04286789 / Completed临床1期

A Randomized, Double-blind, Parallel, Vehicle Controlled, Repeat Dose Comparative Phase 1b Study to Evaluate the Safety, Tolerability and Pharmacokinetics of ORTD-1 in Rheumatoid Arthritis Patients With Mild Disease Managed With DMARDs

This is a randomized, vehicle controlled, double-blind, repeat dose comparative study in patients with rheumatoid arthritis (RA) under management with DMARDs and with persistent disease activity. The goal of this study is to evaluate the safety, tolerability and pharmacokinetics of 6 weekly repeat doses of ORTD-1.

开始日期2021-03-22

申办/合作机构

Oryn Therapeutics LLC

NCT04295759 / Active, not recruiting临床1期IIT

A Phase I Study of the Adam-10 Inhibitor, INCB7839 in Children With Recurrent/Progressive High-Grade Gliomas to Target Microenvironmental Neuroligin-3

This is a multicenter phase 1 trial of INCB7839 for children with recurrent or progressive high-grade gliomas, including, but not limited to, diffuse intrinsic pontine glioma (DIPG) and other diffuse midline gliomas (DMGs), after upfront therapy.

开始日期2020-07-27

申办/合作机构

National Cancer Institute

100 项与 ADAM17 相关的临床结果

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100 项与 ADAM17 相关的转化医学

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0 项与 ADAM17 相关的专利（医药）

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3,274

项与 ADAM17 相关的文献（医药）

2025-01-01·Current Neuropharmacology

Role of Metalloproteinases in Diabetes-associated Mild Cognitive Impairment

Review

作者: Prather, Jonathan F. ; Nair, Sreejayan ; Pradhanang, Suyasha ; Pereira, Vitoria Mattos

:Diabetes has been linked to an increased risk of mild cognitive impairment (MCI), a condition characterized by a subtle cognitive decline that may precede the development of dementia. The underlying mechanisms connecting diabetes and MCI involve complex interactions between metabolic dysregulation, inflammation, and neurodegeneration. A critical mechanism implicated in diabetes and MCI is the activation of inflammatory pathways. Chronic low-grade inflammation, as observed in diabetes, can lead to the production of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α), interleukin-6 (IL-6), interleukin-1 beta (IL-1β), and interferon-gamma (IFNγ), each of which can exacerbate neuroinflammation and contribute to cognitive decline. A crucial enzyme involved in regulating inflammation is ADAM17, a disintegrin, and metalloproteinase, which can cleave and release TNF-α from its membrane-bound precursor and cause it to become activated. These processes, in turn, activate additional inflammation-related pathways, such as AKT, NF-κB, NLP3, MAPK, and JAK-STAT pathways. Recent research has provided novel insights into the role of ADAM17 in diabetes and neurodegenerative diseases. ADAM17 is upregulated in both diabetes and Alzheimer's disease, suggesting a shared mechanism and implicating inflammation as a possible contributor to much broader forms of pathology and pointing to a possible link between inflammation and the emergence of MCI. This review provides an overview of the different roles of ADAM17 in diabetes-associated mild cognitive impairment diseases. It identifies mechanistic connections through which ADAM17 and associated pathways may influence the emergence of mild cognitive impairment.

2024-12-01·Cellular and Molecular Life Sciences

iRhom2 regulates ectodomain shedding and surface expression of the major histocompatibility complex (MHC) class I

Article

作者: Bonelli, Simone ; Calligaris, Matteo ; Zito, Giovanni ; Lichtenthaler, Stefan F ; Miele, Monica ; D'apolito, Danilo ; Spanò, Donatella P ; Nuti, Elisa ; Carcione, Claudia ; Müller, Stephan A ; Blobel, Carl P ; Scilabra, Simone D ; Rossello, Armando ; Di Bella, Mariangela ; Amico, Giandomenico

AbstractProteolytic release of transmembrane proteins from the cell surface, the so called ectodomain shedding, is a key process in inflammation. Inactive rhomboid 2 (iRhom2) plays a crucial role in this context, in that it guides maturation and function of the sheddase ADAM17 (a disintegrin and metalloproteinase 17) in immune cells, and, ultimately, its ability to release inflammatory mediators such as tumor necrosis factor α (TNFα). Yet, the macrophage sheddome of iRhom2/ADAM17, which is the collection of substrates that are released by the proteolytic complex, is only partly known. In this study, we applied high-resolution proteomics to murine and human iRhom2-deficient macrophages for a systematic identification of substrates, and therefore functions, of the iRhom2/ADAM17 proteolytic complex. We found that iRhom2 loss suppressed the release of a group of transmembrane proteins, including known (e.g. CSF1R) and putative novel ADAM17 substrates. In the latter group, shedding of major histocompatibility complex class I molecules (MHC-I) was consistently reduced in both murine and human macrophages when iRhom2 was ablated. Intriguingly, it emerged that in addition to its shedding, iRhom2 could also control surface expression of MHC-I by an undefined mechanism. We have demonstrated the biological significance of this process by using an in vitro model of CD8+ T-cell (CTL) activation. In this model, iRhom2 loss and consequent reduction of MHC-I expression on the cell surface of an Epstein-Barr virus (EBV)-transformed lymphoblastoid cell line dampened activation of autologous CTLs and their cell-mediated cytotoxicity. Taken together, this study uncovers a new role for iRhom2 in controlling cell surface levels of MHC-I by a dual mechanism that involves regulation of their surface expression and ectodomain shedding.

2024-12-01·Cellular and Molecular Life Sciences

Pathological mutations reveal the key role of the cytosolic iRhom2 N-terminus for phosphorylation-independent 14-3-3 interaction and ADAM17 binding, stability, and activity

Article

作者: Babendreyer, Aaron ; Knapp, Sarah ; Bläsius, Katharina ; Keller, Diandra ; Grannemann, Caroline ; Düsterhöft, Stefan ; Baron, Jens Malte ; Tacken, Nikola ; Flaßhove, Charlotte ; Gao, Xintong ; Kahveci-Türköz, Selcan ; Ludwig, Andreas ; Huth, Sebastian ; Sonnabend, Friederike ; Ludwig, Lena ; Adrain, Colin

AbstractThe protease ADAM17 plays an important role in inflammation and cancer and is regulated by iRhom2. Mutations in the cytosolic N-terminus of human iRhom2 cause tylosis with oesophageal cancer (TOC). In mice, partial deletion of the N-terminus results in a curly hair phenotype (cub). These pathological consequences are consistent with our findings that iRhom2 is highly expressed in keratinocytes and in oesophageal cancer. Cub and TOC are associated with hyperactivation of ADAM17-dependent EGFR signalling. However, the underlying molecular mechanisms are not understood. We have identified a non-canonical, phosphorylation-independent 14-3-3 interaction site that encompasses all known TOC mutations. Disruption of this site dysregulates ADAM17 activity. The larger cub deletion also includes the TOC site and thus also dysregulated ADAM17 activity. The cub deletion, but not the TOC mutation, also causes severe reductions in stimulated shedding, binding, and stability of ADAM17, demonstrating the presence of additional regulatory sites in the N-terminus of iRhom2. Overall, this study contrasts the TOC and cub mutations, illustrates their different molecular consequences, and reveals important key functions of the iRhom2 N-terminus in regulating ADAM17.

项与 ADAM17 相关的新闻（医药）

2024-10-25

·ioncology

孟岩教授：上海东方肝胆外科医院原发性肝癌放射治疗经验介绍

点击蓝字关注我们编者按原发性肝癌是我国常见的恶性肿瘤之一，其发病率和死亡率分别位居我国恶性肿瘤的第4位和第2位。原发性肝癌的病理类型主要包括肝细胞癌（HCC）、肝内胆管细胞癌和混合型肝癌，其中HCC占85%～90%。HCC的治疗强调多学科（MDT）综合模式，对于可手术HCC，根治性肝切除术或肝移植术是标准的治疗方案；对于不可手术HCC，放射治疗、射频消融（RFA）、经动脉化疗栓塞（TACE）及系统治疗等都是有效治疗手段。近年来随着放疗技术的快速发展，三维适形放疗（3D-CRT）、调强放疗（IMRT）、立体定向放疗（SBRT）及图像引导放疗（IGRT）等技术在肝癌治疗中得到广泛应用。在由中国研究型医院学会精准医学与肿瘤MDT专业委员会主办、清华大学附属北京清华长庚医院承办的“放疗联合免疫肿瘤治疗学习班”上，海军军医大学第三附属医院放疗科孟岩教授分享了上海东方肝胆外科医院在原发性肝癌的放射治疗方面的临床经验和学术进展。女性患者，56岁，原发性肝癌Ia期，针对其尾状叶病灶采用了SBRT治疗。治疗时间为2016年3月10日至3月15日，共计6次照射，在7天内完成，总剂量为42 Gy，生物等效剂量10（BED10）为71.4 Gy。放疗后半年复查结果显示完全缓解（CR）。至今，患者已随访7年，一般情况良好，未见肿瘤复发。整体上，SBRT治疗小肝癌安全有效（表1）。表1.SBRT治疗小肝癌的疗效大体积/伴大血管受侵HCC的放疗孟岩教授团队开展的一项研究[1]旨在对比HCC伴门静脉癌栓（PVTT）患者接受TACE前放疗（即RT+TACE）与TACE后接受放疗（即TACE+RT）的生存结局。2016年8月至2019年12月，本研究对不可切除的HCC伴PVTT患者进行了随机对照试验。患者按1:1的比例随机分配至RT+TACE组或TACE+RT组。主要终点是总生存期（OS）。入组的120例患者被均匀分配至两组。结果显示，在意向治疗（ITT）人群中，RT+TACE组1年、2年和3年的OS率分别为61.7%、27.4%和15.6%，而TACE+RT组分别为45.0%、16.1%和4.7%。与TACE+RT组相比，RT+TACE组的中位OS有所增加，差异具有边缘显著性（15.4个月对比11.5个月，HR=0.68，95%CI：0.46-1.01，P=0.054）。RT+TACE组的中位无进展生存期（PFS）为6.6个月，而TACE+RT组为4.2个月（HR=0.66，95%CI：0.46-0.96，P=0.030）。3个月时的疾病控制率（DCR）分别为86.7%对比66.7%（P=0.017），6个月时分别为61.7%对比46.7%（P=0.099）。亚组分析显示，在III/IV型PVTT患者中，RT+TACE组的OS（HR=0.48；95%CI：0.33-0.99，P=0.048）和PFS（HR=0.55；95%CI：0.33-0.93，P=0.026）均优于TACE+RT组。RT+TACE组有3例患者，TACE+RT组有2例患者发生≥3级不良事件。研究表明，对于HCC伴PVTT患者，TACE前接受RT的生存结局优于TACE后接受RT，这可能成为一种优化的局部治疗手段，进一步提高局部控制率。术前新辅助/转化放射治疗孟岩教授团队开展的一项多中心、前瞻性、随机对照研究[2]揭示，相较于单独手术治疗，术前新辅助/转化放射治疗能显著延长HCC伴PVTT患者的DFS和OS，这一发现为CSCO、NCCN等权威指南提供了重要的更新与补充。研究中采用的3-DCRT技术，以3 Gy×6次的低剂量方案实施，然而结果显示，仍有79.3%的患者未能实现癌栓降期效果，且8.5%的患者出现疾病进展（PD），其中IL-6水平升高被认为是导致放射抵抗的关键因素。鉴于此，当前正积极探索更为优化的放射治疗方案，包括提高放射治疗剂量、结合靶向与免疫治疗策略以及探索SBRT等新型放射治疗方式。术后辅助放疗孟岩教授团队开展的一项研究[3]旨在探究肝部分切除术±取栓术后，接受术后IMRT的HCC伴PVTT患者的疗效。2013年7月至2016年6月期间，连续入组的HCC伴PVTT并行肝部分切除术的患者将其随机分配至对照组和辅助IMRT组。研究两组患者的生存结局。研究共纳入52例患者，随机均分为两组，且两组患者的临床病理资料相当。辅助放疗组中位DFS为9.1个月，中位OS为18.9个月；而对照组的中位DFS与OS分别为4.1个月和10.8个月。辅助IMRT组的1年、2年和3年总生存率分别为76.9%、19.2%和11.5%，均显著高于对照组的26.9%、11.5%和0%（P=0.005）。研究显示，肝部分切除术±取栓术后，接受术后IMRT的HCC伴PVTT患者的总生存期显著延长。临床上，HCC肝切除术中常出现切缘不足的情况，导致局部复发率增加，尤其是在存在微血管侵犯（MVI）的患者中。上海东方肝胆外科医院开展的这项研究[4]旨在探讨针对切缘不足的MVI阳性HCC，SBRT作为辅助治疗的疗效。这是一项单中心随机对照试验。入组对象为接受切缘不足肝切除术的MVI阳性HCC患者，将其随机分配至术后辅助SBRT组或单纯手术（SA）组。SBRT使用CyberKnife®系统配合标记追踪装置，在术后1个月针对切缘进行照射。比较两组患者的DFS和OS，并监测不良事件（AE）。共入组76例患者，每组38例。SBRT组的1年、3年和5年DFS率分别为92.1%、65.8%和56.1%，而SA组分别为76.3%、36.8%和26.3%（P=0.005）。SBRT组的1年、3年和5年OS率分别为100%、89.5%和75.0%，而SA组分别为100.0%、68.4%和53.7%（P=0.053）。每位患者SBRT的总剂量为35 Gy，BED为59.5 Gy。放疗相关AE的总发生率为31.6%，且未发生3级或以上AE。研究表明，对于切缘不足的MVI阳性HCC，切缘SBRT提供了一种安全的辅助治疗手段。它能有效预防局部复发，提高DFS。 PVTT是肝癌预后的主要不良因素之一，在肝癌的临床分期系统中占有重要的权重。为了适应肝癌合并PVTT临床诊疗的发展变化，中国医师协会肝癌专业委员会发布《中国肝癌合并门静脉癌栓诊治指南（2021年版）》，旨在为我国肝癌合并PVTT患者的规范化诊疗提供最新的指导性建议，并推出肝癌合并PVTT治疗路径图（图1）[5]。图1. 肝细胞癌合并门静脉癌栓诊疗路径图 SBRT与免疫治疗一名59岁女性患者，诊断为HCC伴下腔静脉癌栓及双肺转移。经TACE联合靶向治疗2个月后，肝内病灶有所缩小，但癌栓增大，肺内病灶保持稳定，肿瘤标志物甲胎蛋白（AFP）为471 μg/L，异常凝血酶原（PIVKA-II）为587 mAU/ml。随后采用射波刀SBRT治疗，3个月后复查显示肝内肿瘤及癌栓明显缩小，肺转移瘤及纵隔转移淋巴结完全消失，肿瘤标志物恢复正常水平。考虑存在远隔免疫效应（尽管2017年时免疫治疗尚未应用）。术后病理检查确认肝右叶为综合治疗后坏死性肝癌，伴有混合结节型肝硬化及慢性胆囊炎。术后随访6年半，影像学检查及肿瘤标志物检测均维持正常状态。新辅助放疗孟岩教授及其研究团队通过一项RCT[6]，探究了新辅助放疗对于伴有MVI高危因素的、单个且直径不超过5 cm的乙型肝炎病毒（HBV）相关性小肝癌患者的预后影响。主要纳入标准包括：单发肿瘤，最大直径不超过5 cm，无大血管及胆管受累；确诊HBV感染；存在微血管侵犯的高危因素；经综合评估确认可耐受根治性手术切除，且不存在其他手术禁忌证。自2014年10月至2017年1月，共计60例符合条件的患者被纳入并随机以1:1的比例分配至新辅助放疗组（30例）与直接手术组（30例），确保两组间临床病理特征均衡无显著差异。结果显示，新辅助放疗组的ORR为25.0%。安全性方面，新辅助放疗组中观察到2例发生3级及以上毒副作用。ITT中，两组的中位DFS及OS均未达到预设终点，差异无统计学意义（P=0.399）。本研究提示，对于符合条件的小肝癌患者，采用新辅助放疗方案（总剂量300 cGy，分6次治疗）展现出一定的客观肿瘤反应和良好的安全性。然而，与直接手术相比，新辅助低剂量放疗并未能显著提升伴有微血管侵犯高危因素的HBV相关性小肝细胞癌患者的术后生存率。基于这些发现，研究者推测提高剂量强度的放疗及联合靶向免疫疗法可能成为未来肝癌新辅助治疗领域的一个重要发展方向。此外，动物实验[7]结果显示，针对抗PD-1免疫治疗抵抗型的“冷”肿瘤，不同治疗策略的效果存在显著差异。具体而言，单用抗PD-1治疗未能有效激活免疫反应；连续照射结合抗PD-1治疗以及一周内间隔4天的照射加抗PD-1治疗同样未能显著改变“冷”肿瘤状态，免疫激活不明显。相比之下，采用分段递增强度治疗（间隔10天）可能显著激活免疫反应，导致肿瘤明显缩小（P<0.001）。目前，相关课题研究正在进行中，结果值得期待。小结放疗是肝癌各期治疗中的有效手段。对于可手术的肝癌患者，特别是伴有癌栓或属于“中央型肝癌”的病例，建议实施术前新辅助放疗或转化放疗，以及在采用窄切缘切除或MVI阳性术后进行辅助放疗。SBRT不仅能够迅速减小肿瘤负荷，还可能增强免疫治疗的疗效，预示着它可能成为未来肝癌放疗的主导模式。对于晚期肝癌患者，低剂量放疗（LDRT）可通过调节免疫微环境，进一步提升免疫治疗的效果。参考文献：（上下滑动查看更多） 1. Hepatol Int. IF: 5.9Q12022 Dec;16(6):1368-1378. doi: 10.1007/s12072-022-10423-7. Epub 2022 Oct 21 2. J Clin Oncol. 2019 Aug 20;37(24):2141-2151. 3. Radiother Oncol. IF: 4.9Q12019 Nov:140:20-25. doi: 10.1016/j.radonc.2019.05.006. Epub 2019 Jun 5. 4. Eur J Cancer. IF: 7.6Q12022 May:166:176-184. doi: 10.1016/j.ejca.2022.02.012. Epub 2022 Mar 15 5. Liver Cancer. IF: 11.6Q12022 Mar 17;11(4):315-328. doi: 10.1159/000523997. eCollection 2022 Jul. 6. Int J Surg. IF: 12.5Q12023 Oct 1;109(10):3052-3060. 7. Int JRadiat Oncol Biol Phys.2021 August 01;110(5):1306-1316.doi:10.1016/j.jrobp.2021.03.047. 专家简介孟岩中国医师协会肝癌专业委员会放疗委员会副主任委员中华医学会上海肿瘤放射治疗学会委员军队放射肿瘤学会委员中国抗癌学会肝癌治疗学会委员《中国肿瘤临床》等杂志编委海军军医大学第三附属医院（东方肝胆外科医院）放射治疗科教授，主任医师。1987年毕业于原第二军医大学，师从我国著名老一辈放射治疗专家余友渔教授，至今已从事放射肿瘤临床和研究近40年，擅长肝胆、妇科、泌尿及胸部等恶性肿瘤的内、外放射治疗。尤其在复杂肝胆恶性肿瘤的放、化疗结合手术的综合治疗方面具有鲜明的特色。获得军队医疗成果奖一项，上海市科技进步一等奖一项。国内核心期刊发表论文40余篇，SCI 10余篇。获得多项国家、军队和上海市科委基金，“973”科研基金子课题一项。（来源：《国际肝病》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

放射疗法临床结果

2024-10-25

·ioncology

ILCA 2024丨元云飞教授：REFINE研究报道介入治疗亚组数据，真实世界TACE联合靶向治疗有生存获益

编者按：第18届国际肝癌协会（ILCA）年会于2024年10月17—19日在加拿大多伦多举行。本次大会上,美国加州大学洛杉矶分校（UCLA）大卫·格芬医学院的Richard S. Finn教授再次报道了真实世界REFINE研究的亚组分析，结果表明在接受瑞戈非尼治疗的不可切除肝细胞癌（uHCC）患者中，接受过经动脉化疗栓塞（TACE）和经动脉放射栓塞（TARE）的患者具有更好的生存获益趋势。《肿瘤瞭望》特邀中山大学肿瘤防治中心元云飞教授介绍和点评该研究如下。研究简介在常规临床实践中接受瑞戈非尼治疗的不可切除肝细胞癌患者的观察性研究（REFINE）：根据先前的经动脉化疗栓塞（TACE）和经动脉放射栓塞（TARE）的亚组分析背景瑞戈非尼被批准用于治疗不可切除肝细胞癌（uHCC）患者，这些患者在接受索拉非尼治疗后发生病情进展，这一批准是基于 III期RESORCE试验中总生存期（OS）改善。国际前瞻性观察性研究REFINE研究（NCT03289273）证实了瑞戈非尼在广泛uHCC患者群体中的安全性和有效性，这与RESORCE的结果一致。这项REFINE研究的亚组分析根据先前的经动脉化疗栓塞（TACE）和经动脉放射栓塞（TARE）对患者进行了评估。方法 REFINE研究包括了由医生在登记前决定使用瑞戈非尼治疗的uHCC患者，且符合当地卫生当局批准的标签。主要目标是评估安全性（根据MedDRA v25编码；根据NCI CTCAE v4.03分级）以及由于治疗紧急不良事件（TEAEs）导致的剂量调整。次要终点包括OS和治疗持续时间（DoT）。结果共有1005例患者可供评估。基线时，中位年龄为66岁，83%为男性，62%为BCLC C期，82%的ECOG PS为0或1，55%来自亚洲。大多数患者曾接受过索拉非尼治疗（96%），10%的患者曾接受过免疫检查点抑制剂。大多数患者（58%）既往接受过TACE，3%的患者接受过TARE。在接受过TACE的患者中，68%来自亚洲，而只有29%接受过TARE的患者来自亚洲。总体而言，基线特征在亚组间是一致的。接受过TACE或TARE治疗的患者的整体安全性概况与未接受过的患者相似。接受过TACE治疗的患者具有更长的中位OS（log-rank P = 0.03），中位OS（95% CI）达到了41.7个月（38.7, 45.5）。接受过TARE相关的OS益处的趋势也相似（log-rank P = 0.47），中位OS（95% CI）为35.1个月（25.7, 51.2）。结论在瑞戈非尼治疗的患者中，与没有接受过TACE的患者相比，接受过TACE治疗的患者具有OS获益。这种趋势在接受过TARE治疗的患者中也较明显，尽管分析中的患者数量很少。研究点评瑞戈非尼是一种口服的多激酶抑制剂，可阻断肿瘤生长和进展过程中的多种蛋白激酶，包括血管形成（VEGFR1—3、TIE2）、肿瘤增殖（KIT、RET、RAF-1、BRAF）、肿瘤微环境（VEGFR3、PDGFR、FGFR）以及肿瘤免疫（CSF1R）的激酶。国际多中心3期RESORCE研究[2]的阳性结果，使得瑞戈非尼成为第一个获批的uHCC二线靶向治疗药物，真实世界REFINE研究[3]进一步验证了瑞戈非尼的疗效和安全性。RESORCE研究发表至今已过去7年（Lancet,2017），在此期间，国内外进行了大量的中晚期HCC介入联合系统治疗的探索，其中TACE联合靶向治疗是较为常见的探索方案。理论上，TACE等介入治疗除了能够降低肿瘤负荷以外，还可以和靶向治疗、免疫治疗发挥协同抗肿瘤作用，主要由于这些综合治疗手段能够促进肿瘤血管正常化、改善免疫微环境和促进肿瘤抗原的释放[4-5]。因此，在TACE治疗基础上联合靶向、免疫等系统治疗，或可进一步提高疗效和增加生存获益。这次ILCA报道的REFINE研究亚组分析再次验证了这一理念，在瑞戈非尼治疗的患者中，接受过TACE或TARE的患者表现出更好的生存获益。联合治疗的耐受性是临床较为关注的问题之一，在这项研究中，总体上接受过或未接受过TACE（50% vs 58%）患者的≥3级治疗期间不良事件（TEAEs）发生率相当，表明TACE联合瑞戈非尼没有增加不良反应。当然，这是一项真实世界研究，具体的介入治疗时机、次数等情况并不清楚，但总体上患者是可以耐受的，接受过或未接受过TACE（30% vs 32%）患者的停药率相当。国内曾回顾性报道过瑞戈非尼联合TACE用于uHCC二线治疗，结果显示有较好的ORR（42.3%）和DCR（66.1%），仅有9例患者出现3/4级不良反应[6]。这些结果都验证了TACE联合瑞戈非尼用于晚期HCC治疗的可行性。随着靶向、免疫治疗的发展，近年来有了更多的TACE联合治疗探索，尤其是TACE作为中期HCC治疗标准，在此基础上联合靶向、免疫治疗已经积累了丰富的循证医学证据。例如，今年ESMO大会报道的3期LEAP-012研究[7]中，在TACE基础上联合“可乐组合”（帕博利珠单抗＋仑伐替尼）用于中期肝癌可显著改善无进展生存期（PFS：14.6 vs 10.0个月；HR 0.66，P=0.0002）；而既往报道的3期EMERALD-1研究[8]中，局晚期肝癌患者在TACE基础上联合“D+B”（度伐利尤单抗＋贝伐珠单抗），同样可以显著改善PFS（15.0 vs 8.2个月，HR 0.77，P=0.032）。综上所述，TACE等介入治疗与靶向、免疫联合治疗具有良好的协同增效机制，随着药物组合的丰富以及治疗范围的拓展，该联合治疗方案有望为HCC带来更多治疗变革，造福更多患者。参考文献上下滑动查看更多内容 [1]Richard S. Finn, et al.OBSERVATIONAL STUDY OF PATIENTS WITH UNRESECTABLE HEPATOCELLULAR CARCINOMA TREATED WITH REGORAFENIB IN ROUTINE CLINICAL PRACTICE (REFINE): SUBGROUP ANALYSIS BY PRIOR TRANSARTERIAL CHEMOEMBOLIZATION (TACE) AND TRANSARTERIAL RADIOEMBOLIZATION (TARE).ILCA 2024;P-69 [2]Bruix J, Qin S, Merle P, et al. Regorafenib for patients with hepatocellular carcinoma who progressed on sorafenib treatment (RESORCE): a randomised, double-blind, placebo-controlled, phase 3 trial [published correction appears in Lancet. 2017 Jan 7;389(10064):36. doi: 10.1016/S0140-6736(16)32615-0]. Lancet. 2017;389(10064):56-66. doi:10.1016/S0140-6736(16)32453-9 [3]Richard S. Finn,et al.Real-world dosing of regorafenib in patients with unresectable hepatocellular carcinoma (uHCC): Final analysis of the prospective, observational REFINE study. Journal of Clinical Oncology,Volume 41, Number 4_suppl. https://doi.org/10.1200/JCO.2023.41.4_suppl.518 [4]Perfahl H, Jain HV, Joshi T, et al. Hybrid Modelling of Transarterial Chemoembolisation Therapies (TACE) for Hepatocellular Carcinoma (HCC). Sci Rep. 2020;10(1):10571. Published 2020 Jun 29. doi:10.1038/s41598-020-65012-1 [5]Tachiiri T, Nishiofuku H, Maeda S, et al. Vascular Normalization Caused by Short-Term Lenvatinib Could Enhance Transarterial Chemoembolization in Hepatocellular Carcinoma. Curr Oncol. 2023;30(5):4779-4786. Published 2023 May 5. doi:10.3390/curroncol30050360 [6]Wang H, Xiao W, Han Y, et al. Study on safety and efficacy of regorafenib combined with transcatheter arterial chemoembolization in the treatment of advanced hepatocellular carcinoma after first-line targeted therapy. J Gastrointest Oncol. 2022;13(3):1248-1254. doi:10.21037/jgo-22-395 [7]Llovet JM, et al. Transarterial chemoembolization (TACE) with or without lenvatinib (len) +pembrolizumab (pembro) for intermediate-stage hepatocellular carcinoma (HCC): Phase III LEAP-012 study.2024ESMO LBA3. [8]Riccardo Lencioni,et al.EMERALD-1: A phase 3, randomized, placebo-controlled study of transarterial chemoembolization combined with durvalumab with or without bevacizumab in participants with unresectable hepatocellular carcinoma eligible for embolization.Journal of Clinical Oncology,Volume 42, Number 3_suppl.https://doi.org/10.1200/JCO.2024.42.3_suppl.LBA432 元云飞教授中山大学二级教授、二级研究员、一级主任医师、博士生导师中山大学附属肿瘤医院肝脏外科主诊教授华南恶性肿瘤防治全国重点实验室PI 专长：肝脏肿瘤的外科治疗和介入治疗中国医师协会外科医师分会肝脏外科专家工作组专家委员广东省抗癌协会肿瘤转移专业委员会主任委员广东省临床医学学会肝癌与肝转移瘤专业委员会主任委员《Cancer Communications》编委《中华普通外科学文献电子版》编委《中华肝脏外科手术学电子版》编委《岭南现代临床外科》编委（来源：《肿瘤瞭望》编辑部）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

临床结果临床3期申请上市临床研究

2024-10-17

·PipelineReview

SciRhom Initiates Dosing in First-in-Man Clinical Study Evaluating theCompany’s Lead Development Program SR-878

Transition into clinical-stage development marks a significant corporate and R&D milestone . MUNICH, Germany I October 17, 2024 I SciRhom GmbH, a biopharmaceutical company pioneering the development of first-in-class therapeutic iRhom2 antibodies, today announced that the dosing of participants has commenced in the first clinical study evaluating the company’s most advanced development program SR-878. The first-in-human, double-blind, placebo-controlled, single ascending dose study will assess the safety, tolerability, pharmacokinetic, and pharmacodynamic effects of SR-878 in up to 48 healthy volunteers. SciRhom is conducting the study in collaboration with the Department of Clinical Pharmacology at the Medical University of Vienna, Austria. The study is expected to read out in H2 2025. “ Initiating the first clinical study with our iRhom2-targeting approach represents a transformational milestone and value inflection point for the company. Our goal is to underpin the favorable safety profile of SR-878 observed in preclinical studies, and progress swiftly toward demonstrating the clinical benefits of our novel approach in patients in the subsequent Phase 2 trials, ” commented Dr. Jürgen Reess, CMO of SciRhom. Dr. Jan Poth, Managing Director & CEO of SciRhom added: “ Today’s exciting event brings us closer than ever before to demonstrating the breakthrough potential of targeting iRhom2 and thereby modulating the disease-relevant pathways controlled by TACE/ADAM17. We are very happy that we could engage the Department of Clinical Pharmacology at the Medical University of Vienna for this first study in humans, whose expertise will be very valuable in establishing a solid foundation for potentially multiple subsequent studies. ” With its SR-878 program, SciRhom aims to provide a new treatment paradigm for autoimmunediseases and potentially other indications by simultaneously blocking several pro-inflammatoryand disease-driving pathways. The highly selective engagement of iRhom2 is expectedto lead to superior efficacy compared to currently available treatments while preservingother vital functions of iRhom2’s interaction partner TACE/ADAM17, which should contributeto a favorable safety profile. About iRhom2 TACE (TNF-alpha converting enzyme, also known as ADAM17) controls several major signaling pathways, including TNF-alpha, IL-6R, and EGFR signaling. TACE is therefore widely accepted as a potential target to block pro-inflammatory pathways, but direct inhibition of TACE causes severe side effects. The more recent discovery that iRhom2 (inactive Rhomboid 2, RHBDF2) simultaneously and very specifically regulates the TACE-dependent release of TNF-alpha and other pro-inflammatory molecules from immune cells provides the exciting opportunity to target the disease-driving activities of TACE while preserving its other vital functions. Given the pivotal role of iRhom2, numerous new research studies have recently highlighted the therapeutic potential of targeting iRhom2 to treat immunological and inflammatory diseases and beyond, including oncological, infectious, and metabolic diseases. About SciRhom GmbH At SciRhom, we are translating world-leading expertise in the TACE/ADAM17 pathway and its central role in autoimmunity and other indications into breakthrough biopharmaceuticals. We are developing proprietary and first-in-class iRhom2-targeting therapies and are accelerating our lead antibody program SR-878 into and through clinical development. With strong support from international lead investors Andera Partners, Kurma Partners, Hadean Ventures, MIG Capital, Wellington Partners, as well as Bayern Kapital and current shareholders, SciRhom aims to push the boundaries in autoimmune medicine. For further information, please visit www.SciRhom.com SOURCE: SciRhom