首页 > 最新文献

Cancer Communications最新文献

英文 中文
In vivo intratumoral heterogeneity in a dish: scalable forebrain organoid models of embryonal brain tumors for high-throughput personalized drug discovery 培养皿中的体内肿瘤内异质性：用于高通量个性化药物发现的胚胎性脑肿瘤的可扩展前脑类器官模型。
IF 24.9 1区 医学 Q1 ONCOLOGY
Cancer Communications
Pub Date : 2025-11-02 DOI: 10.1002/cac2.70074
Nicole C. Riedel, Carolin Walter, Flavia W. de Faria, Lea Altendorf, Paula Aust, Carolin Göbel, Archana Verma, Annika Ballast, Ivan Bedzhov, Rajanya Roy, Daniel Münter, Erik Schüftan, Thomas K. Albert, Claudia Rössig, Pascal Johann, Barbara von Zezschwitz, Sarah Sandmann, Julian Varghese, Christian Thomas, Ulrich Schüller, Jan M. Bruder, Kornelius Kerl
<p>Brain tumors are the most prevalent solid tumors in pediatrics, with atypical teratoid and rhabdoid tumor (ATRT) and embryonal tumor with multilayered rosettes (ETMR) presenting particularly poor prognoses.</p><p>The development of effective therapies is hampered by the lack of in vitro models that accurately reflect the complex tumor microenvironment (TME) and intratumoral heterogeneity observed in vivo. Traditional monolayer and tumorsphere/tumoroid cultures fail to capture these critical aspects [<span>1</span>], biasing them towards proliferative cell populations that respond differently to drugs than the original tumor. Likewise, in vivo models have fundamental limitations: they lack the primate-specific chromosome 19 microRNA cluster (C19MC) driver central to ETMR [<span>2</span>], cannot capture human-specific neurotoxicity, and are impractical for scalable drug screens [<span>1, 3</span>].</p><p>To address this, we developed a scalable and reproducible tumor-forebrain-organoid (TBO) model for ETMR and ATRT sonic hedgehog (ATRT-SHH) using a novel coaggregation method, which we characterized histologically and transcriptionally, and applied to drug screening, thereby identifying new candidate therapeutics for ETMR (Supplementary File of Methods). The automated workflow ensures high reproducibility and scalability, enabling the parallel generation of thousands of TBOs for high-throughput drug screening on tumor and TME.</p><p>To integrate central nervous system embryonal tumors into forebrain organoids (FBOs), which recapitulate key developmental trends and contain comparable cell populations found in first- and second-trimester fetal brains, we modified an automated FBO model [<span>4</span>] (Supplementary Figures S1, S3). For this, we employed a coaggregation approach, which involved mixing tumor and human-induced pluripotent stem cells (hiPSCs), and subsequently allowing their aggregation and joint maturation to form TBOs (Figure 1A). Confocal microscopy of whole-mount immunostained and cleared organoids revealed a broad and uniform integration of green fluorescent protein (GFP)-tagged human ETMR and ATRT-SHH (hETMR and hATRT-SHH) cells throughout FBOs (Figure 1B). The automated workflow allowed for the parallel generation of highly uniform and reproducible TBOs in 96-well plates, with low-standard error of the mean for the GFP signal intensity, indicative for tumor content, across multiple TBOs for both hETMR-FBO and hATRT-SHH-FBO (Figure 1C).</p><p>To comprehensively characterize TBOs, we employed immunohistochemistry (IHC) to examine the phenotype of hETMR- and hATRT-SHH-FBOs, with age-matched FBOs as controls. hETMR tumor areas were identified based on lin-28 homolog A (LIN28A) positivity, multilayered rosettes, and C19MC alterations, along with GFP immunofluorescence (Figure 1D, Supplementary Figure S4A-D). Control 1-month aged FBOs exhibited a predominantly immature phenotype [LIN28A<sup>+</sup>, SRY-box transcription factor 2 (
脑肿瘤是儿科最常见的实体肿瘤，非典型畸胎瘤和横纹肌样瘤（ATRT）和具有多层玫瑰花结的胚胎性肿瘤（ETMR）预后特别差。由于缺乏准确反映体内观察到的复杂肿瘤微环境（TME）和肿瘤内异质性的体外模型，阻碍了有效治疗方法的发展。传统的单层和肿瘤球/类肿瘤培养不能捕获这些关键方面，使它们偏向于对药物反应不同于原始肿瘤的增殖细胞群。同样，体内模型也有基本的局限性：它们缺乏灵长类动物特异性的19号染色体microRNA簇（C19MC）驱动程序，对ETMR[2]至关重要，不能捕获人类特异性的神经毒性，并且无法用于可扩展的药物筛选[1,3]。为了解决这个问题，我们使用一种新的共聚集方法开发了一种可扩展和可重复的肿瘤-前脑-类器官（TBO）模型，用于ETMR和ATRT音猬（ATRT- shh），我们对其进行了组织学和转录表征，并应用于药物筛选，从而确定了ETMR的新候选治疗方法（方法补充文件）。自动化工作流程确保了高再现性和可扩展性，能够并行生成数千个tbo，用于肿瘤和TME的高通量药物筛选。为了将中枢神经系统胚胎肿瘤整合到前脑类器官（FBOs）中，这概括了关键的发育趋势，并包含在妊娠早期和妊娠中期胎儿大脑中发现的可比较的细胞群，我们修改了一个自动化的FBO模型[4]（补充图S1， S3）。为此，我们采用了一种共聚集方法，将肿瘤细胞和人类诱导的多能干细胞（hiPSCs）混合在一起，随后允许它们聚集和关节成熟形成tbo（图1A）。全贴载免疫染色和清除类器官的共聚焦显微镜显示，绿色荧光蛋白（GFP）标记的人ETMR和ATRT-SHH （hETMR和hATRT-SHH）细胞在整个fbo中广泛而均匀地整合（图1B）。自动化工作流程允许在96孔板上并行生成高度均匀和可重复的tbo，在hETMR-FBO和hatrt - sh - fbo的多个tbo中，GFP信号强度的平均标准误差很低，指示肿瘤含量（图1C）。为了全面表征TBOs，我们采用免疫组织化学（IHC）检测了hETMR-和hatrt - sh -FBOs的表型，并以年龄匹配的FBOs为对照。基于lin-28同源物A （LIN28A）阳性、多层莲座、C19MC改变以及GFP免疫荧光鉴定hETMR肿瘤区域（图1D，补充图S4A-D）。对照1月龄FBOs在培养过程中（2-3月龄时为MAP2C+、SOX2 -、LIN28A -）成熟，表型以不成熟为主[LIN28A+、SRY-box转录因子2 +、微管相关蛋白2C+]。hETMR细胞在所有时间点上一致显示未成熟祖细胞标记物（LIN28A+、SOX2+和Nestin+）阳性（图1D，补充图S4A-D）。此外，很少有hETMR细胞表现出细胞质MAP2C阳性。对于hATRT-SHH，根据IHC中SWI/ snf相关基质相关动作蛋白依赖的染色质亚家族B成员1的调节因子（SMARCB1）阴性（ATRT的标志）和免疫荧光中GFP阳性（图1E，补充图S4E-F）来确定肿瘤区域。值得注意的是，hart - shh细胞sox2阳性，部分map2c阳性（图1E，补充图S4E-F）。hETMR和hATRT-SHH细胞主要表现为不成熟表型（SOX2+，少数MAP2C+细胞）。与原发肿瘤一致，它们表现出特定的特征：hETMR中C19MC扩增和多层花环，而hATRT中SMARCB1阴性。最近的研究强调了在体内观察到的ETMR[5]和ATRT[6]的肿瘤内转录异质性，这种异质性在肿瘤细胞系中没有反映出来（补充图S5）。为了评估我们的tbo是否能更好地反映原发肿瘤细胞与肿瘤球的肿瘤内异质性，我们进行了单细胞RNA测序（scRNA-seq），并将我们的数据与公开的原发肿瘤数据集相结合[5-7]。对于ETMR，我们将肿瘤细胞分为放射状胶质样（RG-like）、神经元祖细胞样（NProg-like）和神经母细胞样（Nb-like）亚组，所有亚群都出现在hETMR-FBO中（图1F，补充图S6A-B）。相比之下，肿瘤球培养在hETMR中主要表现为nprog样细胞，在mETMR中主要表现为循环rg样细胞，这表明与tbo和初级样品中观察到的转录景观不同（图1G，补充图S6C-G）。 对于hATRT-SHH，我们采用基于特征的方法，使用胎儿前脑图谱[8]的神经元特征，将hATRT-SHH细胞分为类似于胎儿放射状胶质细胞（RG）、神经元祖细胞（NProg）和神经母细胞（Nb）的亚组，并将其余细胞分类为未分化细胞（图1H，补充图S6H-I）。值得注意的是，原代和TBO肿瘤细胞在亚群中表现出平衡分布，而肿瘤球培养则表现出向nprog样状态倾斜的分布（图1I）。此外，指示神经元分化的标记基因，如statthmin 2 (STMN2)，在瘤球nb样细胞中明显缺失（Supplementary Figure S6J）。随后的细胞周期动力学分析显示，与tbo相比，肿瘤球表现出循环细胞的积累，后者表现出与初级样品相似的动力学（补充图S7）。Pearson相关分析进一步证实，与原发肿瘤和肿瘤球相比，原发肿瘤与TBO之间的相关性更高（图1J-K，补充图S8A-B），强调TBO在再现原发肿瘤转录格局方面具有更高的保真度。差异表达分析揭示了肿瘤球和tbo之间基因表达模式的显著变化（补充图S8C-D），表明神经组织环境对肿瘤细胞表型有上下文影响。利用我们的TBO模型同时宿主肿瘤和神经元细胞的独特能力，我们建立了一个细胞类型特异性药物筛选的自动化工作流程。TBO形成和发展后，于第20天开始药物治疗，第30天固定TBO进行后续分析，然后进行全挂载免疫染色、组织清除和高含量成像（图1L）。作为概念验证，我们通过评估依托opo苷对小鼠ETMR肿瘤（黄色荧光蛋白；YFP+）和神经元（MAP2C+） FBO细胞的作用，确定了依托opo苷的治疗窗口，该浓度范围最大限度地提高了抗肿瘤功效，同时最小化了神经元毒性（补充图S9）。在确定了tbo中细胞类型特异性毒性筛选的可行性后，我们接下来筛选了美国食品药品监督管理局批准的160种hetmr - fbo药物库（补充表S1），以确定新的药物脆弱性。大多数化合物对肿瘤的毒性高于对TME细胞的毒性（补充图S10）。有趣的是，我们筛选的四种高分药物（图1M），阿霉素、柔红霉素、长春新碱和阿糖胞苷，目前正在临床试验中作为治疗ETMR的新疗法进行研究[9,10]。三种具有高抗肿瘤活性和低神经毒性的候选药物——雷公藤甲素、阿霉素和柔红霉素的剂量-反应曲线验证了它们的抗肿瘤作用（减少GFP+细胞），并评估了它们对MAP2C+神经细胞的毒性（图1N-P）。值得注意的是，雷公藤甲素具有显著的抗肿瘤活性，且神经元毒性相对较低。正在进行ETMR临床研究的蒽环类药物（阿霉素和柔红霉素）的鉴定[9,10]，通过使用PERCEPTION（见方法）的独立计算分析进一步验证，预测蒽环类药物对原发性ETMR的疗效很高（补充图S11）。这一发现加强了我们筛选平台的预测有效性。总之，我们使用一种简单、自动化的共聚集方法建立了ETMR-和atrt - sh - fbo模型，与传统的肿瘤球相比，该方法能更好地概括原发肿瘤的组织学特征和转录异质性。我们的研究验证了细胞类型特异性药物筛选的方法，并确定了蒽环
{"title":"In vivo intratumoral heterogeneity in a dish: scalable forebrain organoid models of embryonal brain tumors for high-throughput personalized drug discovery","authors":"Nicole C. Riedel,&nbsp;Carolin Walter,&nbsp;Flavia W. de Faria,&nbsp;Lea Altendorf,&nbsp;Paula Aust,&nbsp;Carolin Göbel,&nbsp;Archana Verma,&nbsp;Annika Ballast,&nbsp;Ivan Bedzhov,&nbsp;Rajanya Roy,&nbsp;Daniel Münter,&nbsp;Erik Schüftan,&nbsp;Thomas K. Albert,&nbsp;Claudia Rössig,&nbsp;Pascal Johann,&nbsp;Barbara von Zezschwitz,&nbsp;Sarah Sandmann,&nbsp;Julian Varghese,&nbsp;Christian Thomas,&nbsp;Ulrich Schüller,&nbsp;Jan M. Bruder,&nbsp;Kornelius Kerl","doi":"10.1002/cac2.70074","DOIUrl":"10.1002/cac2.70074","url":null,"abstract":"&lt;p&gt;Brain tumors are the most prevalent solid tumors in pediatrics, with atypical teratoid and rhabdoid tumor (ATRT) and embryonal tumor with multilayered rosettes (ETMR) presenting particularly poor prognoses.&lt;/p&gt;&lt;p&gt;The development of effective therapies is hampered by the lack of in vitro models that accurately reflect the complex tumor microenvironment (TME) and intratumoral heterogeneity observed in vivo. Traditional monolayer and tumorsphere/tumoroid cultures fail to capture these critical aspects [&lt;span&gt;1&lt;/span&gt;], biasing them towards proliferative cell populations that respond differently to drugs than the original tumor. Likewise, in vivo models have fundamental limitations: they lack the primate-specific chromosome 19 microRNA cluster (C19MC) driver central to ETMR [&lt;span&gt;2&lt;/span&gt;], cannot capture human-specific neurotoxicity, and are impractical for scalable drug screens [&lt;span&gt;1, 3&lt;/span&gt;].&lt;/p&gt;&lt;p&gt;To address this, we developed a scalable and reproducible tumor-forebrain-organoid (TBO) model for ETMR and ATRT sonic hedgehog (ATRT-SHH) using a novel coaggregation method, which we characterized histologically and transcriptionally, and applied to drug screening, thereby identifying new candidate therapeutics for ETMR (Supplementary File of Methods). The automated workflow ensures high reproducibility and scalability, enabling the parallel generation of thousands of TBOs for high-throughput drug screening on tumor and TME.&lt;/p&gt;&lt;p&gt;To integrate central nervous system embryonal tumors into forebrain organoids (FBOs), which recapitulate key developmental trends and contain comparable cell populations found in first- and second-trimester fetal brains, we modified an automated FBO model [&lt;span&gt;4&lt;/span&gt;] (Supplementary Figures S1, S3). For this, we employed a coaggregation approach, which involved mixing tumor and human-induced pluripotent stem cells (hiPSCs), and subsequently allowing their aggregation and joint maturation to form TBOs (Figure 1A). Confocal microscopy of whole-mount immunostained and cleared organoids revealed a broad and uniform integration of green fluorescent protein (GFP)-tagged human ETMR and ATRT-SHH (hETMR and hATRT-SHH) cells throughout FBOs (Figure 1B). The automated workflow allowed for the parallel generation of highly uniform and reproducible TBOs in 96-well plates, with low-standard error of the mean for the GFP signal intensity, indicative for tumor content, across multiple TBOs for both hETMR-FBO and hATRT-SHH-FBO (Figure 1C).&lt;/p&gt;&lt;p&gt;To comprehensively characterize TBOs, we employed immunohistochemistry (IHC) to examine the phenotype of hETMR- and hATRT-SHH-FBOs, with age-matched FBOs as controls. hETMR tumor areas were identified based on lin-28 homolog A (LIN28A) positivity, multilayered rosettes, and C19MC alterations, along with GFP immunofluorescence (Figure 1D, Supplementary Figure S4A-D). Control 1-month aged FBOs exhibited a predominantly immature phenotype [LIN28A&lt;sup&gt;+&lt;/sup&gt;, SRY-box transcription factor 2 (","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1670-1675"},"PeriodicalIF":24.9,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728470/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145430387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
A practical overview and statistical analysis of interval-censored data in cancer 癌症中间隔截除数据的实用概述和统计分析。
IF 24.9 1区 医学 Q1 ONCOLOGY
Cancer Communications
Pub Date : 2025-11-02 DOI: 10.1002/cac2.70073
Tanujit Dey, Stuart Lipsitz, Zara Cooper, Debajyoti Sinha, Quoc-Dien Trinh, Alexander Cole, Timothy N. Clinton
<p>In many clinical, biomedical, and epidemiologic cancer studies, the outcome of interest is the time until an event (or failure) occurs, and “survival analysis” is performed to estimate the effect of covariates on survival. Most clinical investigators are familiar with the term “right censoring”. The type of censoring we focus on in this paper is “interval-censoring” [<span>1-3</span>]. Interval-censoring occurs when the event of interest cannot be easily observed but is determined by imaging and/or blood biomarker tests at clinic visits. For example, suppose a patient comes in for imaging every 3 months, to detect the event (cancer recurrence). If recurrence is found at a visit, it occurred sometime between that visit and the previous visit where no recurrence was detected—this is “interval-censoring”. Researchers often code the event date as the visit when recurrence is detected, but this overestimates time to recurrence since it occurred earlier within the interval. Modern statistical software supports proper interval-censoring methods, making it unnecessary to use visit dates as event dates. Since most cancer recurrences are identified through imaging or biomarker tests at clinic visits, interval-censoring methods should be used, at least as a sensitivity analysis to assess the impact of coding the event date as the visit date when recurrence is detected .</p><p>Consider a study of biochemical recurrence in 260 patients with localized prostate cancer who underwent radical prostatectomy [<span>4</span>]. After surgery, prostate-specific antigen (PSA) levels drop to 0 ng/mL, and recurrence is defined as the time PSA exceeds 0.1 ng/mL. Since PSA is measured only at regular intervals (every 3 or 6 months), the recurrence time is unknown and interval-censored between visits. Clinicians often use the first elevated PSA test as the recurrence date, though the true event occurred between the current and previous visit. An interval-censored Cox model assessed the impact of Gleason score, surgical margin, preoperative PSA, and pathologic stage on recurrence time.</p><p>Parameters of survival models are estimated by maximizing a “likelihood” (ML). A patient with an exact failure time <i>t</i> contributes the probability of failure at <i>t</i> to the likelihood. A patient right-censored at time <i>t</i> contributes the probability of surviving beyond <i>t</i>. An interval-censored patient whose event occurs in the interval (<i>L</i>, <i>U</i>), contributes the probability of failure within that interval. After assuming a survival model (e.g., proportional hazards), the probabilities of failure at a given time (no censoring), between two time points (interval-censoring), or greater than a time point (right-censoring), are easily calculated and used in ML.</p><p>Despite the long history of interval-censoring statistical methodology [<span>1-3</span>], until recently, few software packages were available to analyze interval-censored data in a statistical
在许多临床、生物医学和流行病学癌症研究中，关注的结果是事件（或失败）发生之前的时间，进行“生存分析”是为了估计协变量对生存的影响。大多数临床研究者都熟悉“右审查”这个术语。本文关注的审查类型是“间隔审查”[1-3]。当感兴趣的事件不容易观察到，但在门诊就诊时通过成像和/或血液生物标志物测试确定时，进行间隔审查。例如，假设一个病人每3个月来做一次影像学检查，以检测癌症复发。如果在一次访问中发现复发，则发生在该访问和之前未发现复发的访问之间的某个时间-这是“间隔审查”。研究人员通常将事件日期编码为检测到复发的就诊日期，但这高估了复发的时间，因为它在间隔内发生得更早。现代统计软件支持适当的间隔审查方法，使得没有必要使用访问日期作为事件日期。由于大多数癌症复发是通过临床就诊时的成像或生物标志物测试确定的，因此应该使用间隔审查方法，至少作为一种敏感性分析，以评估在检测到复发时将事件日期编码为就诊日期的影响。考虑一项260例接受根治性前列腺切除术的局限性前列腺癌患者的生化复发研究。手术后，前列腺特异性抗原（PSA）水平降至0 ng/mL，当PSA超过0.1 ng/mL时定义为复发。由于PSA仅在定期间隔（每3或6个月）测量，复发时间是未知的，并且在两次就诊之间进行间隔审查。临床医生通常使用第一次PSA检测升高作为复发日期，尽管真实事件发生在当前和上次就诊之间。间隔剔除的Cox模型评估Gleason评分、手术切缘、术前PSA和病理分期对复发时间的影响。通过最大化“似然”（ML）来估计生存模型的参数。一个病人在t的确切失败时间将t的失败概率贡献给可能性。在时间t进行右截尾的患者贡献了超过t的生存概率。在时间间隔（L， U）中发生事件的间隔截尾患者贡献了该时间间隔内的失败概率。在假设一个生存模型（例如，比例风险）之后，在给定时间（无审查），两个时间点之间（间隔审查）或大于一个时间点（右审查）的失败概率很容易计算并在ml中使用。尽管间隔审查统计方法的历史很长[1-3]，直到最近，很少有软件包可用来分析间隔审查数据在统计上有效的方式。因此，当事件被确定时，事件日期通常被分配到诊所访问日期，允许使用仅支持右审查的生存软件。间隔审查方法现在在SAS 9.4版本（SAS Institute Inc）、R和Stata version 19 （StataCorp）中都很容易获得。在SAS中，过程寿命测试用于间隔截短数据的Kaplan-Meier分析，过程寿命测试用于间隔截短比例风险模型。区间截割数据的Kaplan-Meier曲线可以使用R包Icens（版本1.81.0）进行拟合。区间截尾数据的Cox比例风险模型可以在R包icenReg（版本2.0.16）中估计。在Stata中，intcens和string模块支持估计。在下面的模拟中，我们使用了SAS过程。当使用任何软件程序分析间隔截尾数据时，数据集需要有两个变量，分别对应于上面描述的下端点和上端点（L， U）。例如，如果在6个月的成像中发现事件，而在3个月的前一次访问中没有事件，那么您给软件程序提供端点（3,6）。我们进行了一项小规模模拟，以显示使用Cox模型估算风险比和生存率时可能存在的偏差，该模型采用不同的方法来考虑区间审查。我们基于一项膀胱癌复发随机临床试验（西南肿瘤组[SWOG] S0337[5]）中报告的模型和参数估计来模拟数据集。低级别非肌肉侵袭性膀胱癌患者通常接受经尿道膀胱肿瘤切除术（turt）。在参考的临床试验中，干预组在TURBT后立即膀胱滴注吉西他滨，对照组给予生理盐水。吉西他滨组第4年的复发率（35%）明显低于对照组（47%）。 患者在前2年每3个月进行膀胱镜检查和细胞学检查，此后每6个月进行一次检查，导致复发时间间隔。为了简单起见，我们使用分段指数分布来模拟复发时间数据，校准后大致匹配1年、2年、3年和4年的复发率，两组间的风险比为0.68，与试验结果一致。表1的标题中提供了额外的模拟细节。表1中的模拟研究结果表明，使用区间审查Cox回归对所有数量产生无偏估计。然而，使用区间的上端点作为事件时间可能会高估复发时间，相应地低估在给定时间内复发的百分比。这对于估计在较早的时间点（1年）重复出现的百分比尤其正确。随着访问间隔的增加，低估的情况也越来越严重。虽然在实践中是不现实的，但如果每年只安排随访，那么使用间隔的上端点作为复发时间，1年复发率被严重低估（在两组中约有70%向下偏倚）。即使有6个月的随访间隔（更现实），使用上终点，1年复发率也被大大低估了（在两组中大约有25%的向下偏倚）。值得注意的是，所有方法估计的4年复发率几乎是无偏的。同样，所有方法的风险比估计值都是无偏的。这是意料之中的，因为Cox模型只依赖于事件时间的顺序（排名），而不是它们的确切值。因此，Cox模型中的风险比估计值对使用上终点的敏感性低于生存百分比估计值，这也需要在正确的时间尺度上估计基线生存函数。因此，如果估计风险比，使用Cox模型的上终点似乎没有什么偏差。此外，在收集了大多数随访数据之后（例如第4年），检查较晚的时间点也显示出最小的偏差。由于可能的间隔审查配置（例如，随访之间的时间）和产生数据的潜在生存分布的范围很广，因此很难从小规模模拟研究中得出明确的结论。我们只能提出一般的建议。基于我们的模拟，间隔截尾的Cox模型表现最好。虽然对于频繁的随访，使用随访间隔的上限是可以接受的，但当随访间隔较长，特别是在较早的时间点时，可能会引入偏差。考虑到区间审查方法在统计软件中广泛实施，我们建议使用它们，至少进行敏感性分析，以评估使用简化方法（例如，使用区间的上端点）的影响，特别是如果对早期失败感兴趣。该模拟侧重于估计偏差，而不是确定最佳随访计划，该计划应以复发风险和疾病严重程度为指导。Tanujit Dey：进行统计数据分析；形成研究理念和重点；主导稿件编辑；指导项目，并担任项目联合负责人。Stuart Lipsitz：进行统计数据分析；形成研究理念和重点；主导稿件编辑；指导项目，并担任项目联合负责人。Zara Cooper：参与稿件编辑并提供咨询。Debajyoti Sinha：参与稿件编辑并提供咨询。陈国奠：参与稿件编辑；提供咨询，指导项目。亚历山大·科尔：参与手稿编辑；提供咨询，指导项目。蒂姆·克林顿：参与手稿编辑；提供咨询，指导项目方向。所有作者都阅读并批准了最终的手稿。作者声明他们没有与这项工作相关的利益冲突。作者声明他们没有与这项工作相关的资金。本研究完全使用模拟数据进行；没有使用、生成或分析患者数据。模拟数据集可以根据文中描述的方法进行再现。用于生成数据的仿真代码可根据相应作者的合理要求提供。
{"title":"A practical overview and statistical analysis of interval-censored data in cancer","authors":"Tanujit Dey,&nbsp;Stuart Lipsitz,&nbsp;Zara Cooper,&nbsp;Debajyoti Sinha,&nbsp;Quoc-Dien Trinh,&nbsp;Alexander Cole,&nbsp;Timothy N. Clinton","doi":"10.1002/cac2.70073","DOIUrl":"10.1002/cac2.70073","url":null,"abstract":"&lt;p&gt;In many clinical, biomedical, and epidemiologic cancer studies, the outcome of interest is the time until an event (or failure) occurs, and “survival analysis” is performed to estimate the effect of covariates on survival. Most clinical investigators are familiar with the term “right censoring”. The type of censoring we focus on in this paper is “interval-censoring” [&lt;span&gt;1-3&lt;/span&gt;]. Interval-censoring occurs when the event of interest cannot be easily observed but is determined by imaging and/or blood biomarker tests at clinic visits. For example, suppose a patient comes in for imaging every 3 months, to detect the event (cancer recurrence). If recurrence is found at a visit, it occurred sometime between that visit and the previous visit where no recurrence was detected—this is “interval-censoring”. Researchers often code the event date as the visit when recurrence is detected, but this overestimates time to recurrence since it occurred earlier within the interval. Modern statistical software supports proper interval-censoring methods, making it unnecessary to use visit dates as event dates. Since most cancer recurrences are identified through imaging or biomarker tests at clinic visits, interval-censoring methods should be used, at least as a sensitivity analysis to assess the impact of coding the event date as the visit date when recurrence is detected .&lt;/p&gt;&lt;p&gt;Consider a study of biochemical recurrence in 260 patients with localized prostate cancer who underwent radical prostatectomy [&lt;span&gt;4&lt;/span&gt;]. After surgery, prostate-specific antigen (PSA) levels drop to 0 ng/mL, and recurrence is defined as the time PSA exceeds 0.1 ng/mL. Since PSA is measured only at regular intervals (every 3 or 6 months), the recurrence time is unknown and interval-censored between visits. Clinicians often use the first elevated PSA test as the recurrence date, though the true event occurred between the current and previous visit. An interval-censored Cox model assessed the impact of Gleason score, surgical margin, preoperative PSA, and pathologic stage on recurrence time.&lt;/p&gt;&lt;p&gt;Parameters of survival models are estimated by maximizing a “likelihood” (ML). A patient with an exact failure time &lt;i&gt;t&lt;/i&gt; contributes the probability of failure at &lt;i&gt;t&lt;/i&gt; to the likelihood. A patient right-censored at time &lt;i&gt;t&lt;/i&gt; contributes the probability of surviving beyond &lt;i&gt;t&lt;/i&gt;. An interval-censored patient whose event occurs in the interval (&lt;i&gt;L&lt;/i&gt;, &lt;i&gt;U&lt;/i&gt;), contributes the probability of failure within that interval. After assuming a survival model (e.g., proportional hazards), the probabilities of failure at a given time (no censoring), between two time points (interval-censoring), or greater than a time point (right-censoring), are easily calculated and used in ML.&lt;/p&gt;&lt;p&gt;Despite the long history of interval-censoring statistical methodology [&lt;span&gt;1-3&lt;/span&gt;], until recently, few software packages were available to analyze interval-censored data in a statistical","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1666-1669"},"PeriodicalIF":24.9,"publicationDate":"2025-11-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728475/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145430321","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
The INSPECTOR study: enhanced feasibility for clinical translation of a multi-cancer early detection method based on enzyme-assisted high signal-to-noise ratio sequencing of methylated circulating tumor DNA INSPECTOR研究：基于酶辅助的高信噪比甲基化循环肿瘤DNA测序的多癌早期检测方法的临床翻译的可行性增强。
IF 24.9 1区 医学 Q1 ONCOLOGY
Cancer Communications
Pub Date : 2025-10-30 DOI: 10.1002/cac2.70071
Hui-Yan Luo, Wei Wei, Pansong Li, Qi-Hua Zhang, Zhipeng Zhou, Liang Cui, Yong-Bin Lin, Hong Yang, Xianyu Zhong, Qingfeng Liu, Han Yang, Kong-Jia Luo, Hai-Bo Qiu, Shu-Qiang Yuan, Yuan-Fang Li, Zhi-Wei Zhou, Xiao-Jun Lin, Bo-Kang Cui, Rong-Xin Zhang, Wen-Hua Fan, He Huang, Chun-Yan Lan, Jun-Dong Li, Zhi-Qiang Wang, Bin-Kui Li, Rong-Ping Guo, Jun Tang, Xin Huang, Mian Xi, Yuying Liu, Chuanbo Xie, Shi Chen, Zhi-Hu Li, Yu-Hua Liu, Xiao-Ting Zhang, Qiang Zeng, Xin Yi, Rui-Hua Xu
<div> <section> <h3> Background</h3> <p>Blood-based cell-free DNA (cfDNA) methylation testing has emerged as a promising approach for multi-cancer early detection (MCED), holding the potential to improve cancer survival rates. However, traditional bisulfite-based methods often encounter sensitivity limitations in detecting early-stage malignancies or certain cancer types. In the INSPECTOR study, we developed a MCED and cancer signal origin (CSO) system specifically designed for early-stage or hard-to-detect cancers, including those of the lung, breast, colorectum, liver, esophagus, stomach, pancreas, and ovary.</p> </section> <section> <h3> Methods</h3> <p>We established a comprehensive methylation marker discovery database (<i>n</i> = 6,342) by integrating public datasets (<i>n</i> = 4,699) and in-house samples (<i>n</i> = 1,643), all processed using human TET (hTET) enzyme-assisted whole-methylome sequencing (GM-seq). This enabled the design of a targeted panel encompassing 155,362 methylated CpG sites. Leveraging hTET-assisted high-depth next-generation sequencing (NGS), our blood test achieved a median unique depth of 1,093×. Multicenter case-control cohorts, including various pathological subtypes, were used for training, validation, and independent validation of MCED and CSO models, and to verify the clinical feasibility.</p> </section> <section> <h3> Results</h3> <p>Clinical validation was conducted across multi-center case-control cohorts, including 1,071 participants in the training set, 581 in the validation set, and 824 in the independent validation set. The MCED assay demonstrated robust performance with a specificity of 99.1% and sensitivity of 83.2% in the training set, 99.0% and 81.8% in the validation set, and comparable results in the independent validation set (99.0% specificity, 81.9% sensitivity). Notably, sensitivity reached 65.5% for stage I cancers, 79.7% for stage II, and 71.3% for stages I-II combined. The sensitivities for different cancer types were as follows: esophageal (79.2%), gastric (76.1%), colorectal (86.2%), pancreatic (66.7%), liver (100.0%), lung (72.9%), breast (88.9%), and ovarian (87.9%). The CSO model exhibited strong accuracy, with top-1 cancer origin prediction rates of 87.9% (validation) and 87.4% (independent validation), rising to 95.1% and 94.5% for top-2 predictions, respectively. For stage I cancers specifically, the top-1 accuracy was 85.5%.</p> </section> <section> <h3> Conclusions</h3> <p>These findings underscore the efficacy of the hTET-assisted cfDNA methylation sequencing system across divers
背景：基于血液的游离DNA （cfDNA）甲基化检测已经成为一种很有前途的多种癌症早期检测（MCED）方法，具有提高癌症生存率的潜力。然而，传统的基于亚硫酸盐的方法在检测早期恶性肿瘤或某些癌症类型时经常遇到灵敏度限制。在INSPECTOR研究中，我们开发了一种MCED和癌症信号起源（CSO）系统，专门用于早期或难以检测的癌症，包括肺癌、乳腺癌、结直肠癌、肝癌、食道癌、胃癌、胰腺癌和卵巢癌。方法：通过整合公共数据集（n = 4,699）和内部样本（n = 1,643），采用人TET （hTET）酶辅助全甲基组测序（GM-seq）建立了一个全面的甲基化标记发现数据库（n = 6,342）。这使得设计一个包含155,362个甲基化CpG位点的靶向面板成为可能。利用htet辅助的高深度下一代测序（NGS），我们的血液检测达到了1093 x的中位独特深度。采用包括不同病理亚型在内的多中心病例对照队列，对MCED和CSO模型进行训练、验证和独立验证，验证临床可行性。结果：临床验证是跨多中心病例对照队列进行的，其中训练集1071人，验证集581人，独立验证集824人。MCED检测在训练集中的特异性为99.1%，灵敏度为83.2%，在验证集中的特异性为99.0%，灵敏度为81.8%，在独立验证集中的结果相似（特异性为99.0%，灵敏度为81.9%）。值得注意的是，I期癌症的敏感性为65.5%，II期为79.7%，I-II期合并为71.3%。不同类型肿瘤的敏感性分别为：食管癌（79.2%）、胃癌（76.1%）、结直肠癌（86.2%）、胰腺癌（66.7%）、肝癌（100.0%）、肺癌（72.9%）、乳腺癌（88.9%）、卵巢癌（87.9%）。CSO模型显示出很强的准确性，前1名的癌症起源预测率为87.9%（验证）和87.4%（独立验证），前2名的预测率分别上升到95.1%和94.5%。特别是对于I期癌症，前1名的准确率为85.5%。结论：这些发现强调了htet辅助cfDNA甲基化测序系统在不同癌症类型，特别是在早期阶段的有效性。因此，甲基化cfDNA的酶辅助NGS测试增强了非侵入性血液筛查的临床应用。
{"title":"The INSPECTOR study: enhanced feasibility for clinical translation of a multi-cancer early detection method based on enzyme-assisted high signal-to-noise ratio sequencing of methylated circulating tumor DNA","authors":"Hui-Yan Luo,&nbsp;Wei Wei,&nbsp;Pansong Li,&nbsp;Qi-Hua Zhang,&nbsp;Zhipeng Zhou,&nbsp;Liang Cui,&nbsp;Yong-Bin Lin,&nbsp;Hong Yang,&nbsp;Xianyu Zhong,&nbsp;Qingfeng Liu,&nbsp;Han Yang,&nbsp;Kong-Jia Luo,&nbsp;Hai-Bo Qiu,&nbsp;Shu-Qiang Yuan,&nbsp;Yuan-Fang Li,&nbsp;Zhi-Wei Zhou,&nbsp;Xiao-Jun Lin,&nbsp;Bo-Kang Cui,&nbsp;Rong-Xin Zhang,&nbsp;Wen-Hua Fan,&nbsp;He Huang,&nbsp;Chun-Yan Lan,&nbsp;Jun-Dong Li,&nbsp;Zhi-Qiang Wang,&nbsp;Bin-Kui Li,&nbsp;Rong-Ping Guo,&nbsp;Jun Tang,&nbsp;Xin Huang,&nbsp;Mian Xi,&nbsp;Yuying Liu,&nbsp;Chuanbo Xie,&nbsp;Shi Chen,&nbsp;Zhi-Hu Li,&nbsp;Yu-Hua Liu,&nbsp;Xiao-Ting Zhang,&nbsp;Qiang Zeng,&nbsp;Xin Yi,&nbsp;Rui-Hua Xu","doi":"10.1002/cac2.70071","DOIUrl":"10.1002/cac2.70071","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Blood-based cell-free DNA (cfDNA) methylation testing has emerged as a promising approach for multi-cancer early detection (MCED), holding the potential to improve cancer survival rates. However, traditional bisulfite-based methods often encounter sensitivity limitations in detecting early-stage malignancies or certain cancer types. In the INSPECTOR study, we developed a MCED and cancer signal origin (CSO) system specifically designed for early-stage or hard-to-detect cancers, including those of the lung, breast, colorectum, liver, esophagus, stomach, pancreas, and ovary.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We established a comprehensive methylation marker discovery database (&lt;i&gt;n&lt;/i&gt; = 6,342) by integrating public datasets (&lt;i&gt;n&lt;/i&gt; = 4,699) and in-house samples (&lt;i&gt;n&lt;/i&gt; = 1,643), all processed using human TET (hTET) enzyme-assisted whole-methylome sequencing (GM-seq). This enabled the design of a targeted panel encompassing 155,362 methylated CpG sites. Leveraging hTET-assisted high-depth next-generation sequencing (NGS), our blood test achieved a median unique depth of 1,093×. Multicenter case-control cohorts, including various pathological subtypes, were used for training, validation, and independent validation of MCED and CSO models, and to verify the clinical feasibility.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Clinical validation was conducted across multi-center case-control cohorts, including 1,071 participants in the training set, 581 in the validation set, and 824 in the independent validation set. The MCED assay demonstrated robust performance with a specificity of 99.1% and sensitivity of 83.2% in the training set, 99.0% and 81.8% in the validation set, and comparable results in the independent validation set (99.0% specificity, 81.9% sensitivity). Notably, sensitivity reached 65.5% for stage I cancers, 79.7% for stage II, and 71.3% for stages I-II combined. The sensitivities for different cancer types were as follows: esophageal (79.2%), gastric (76.1%), colorectal (86.2%), pancreatic (66.7%), liver (100.0%), lung (72.9%), breast (88.9%), and ovarian (87.9%). The CSO model exhibited strong accuracy, with top-1 cancer origin prediction rates of 87.9% (validation) and 87.4% (independent validation), rising to 95.1% and 94.5% for top-2 predictions, respectively. For stage I cancers specifically, the top-1 accuracy was 85.5%.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;These findings underscore the efficacy of the hTET-assisted cfDNA methylation sequencing system across divers","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1645-1665"},"PeriodicalIF":24.9,"publicationDate":"2025-10-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728497/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145399604","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Intranuclear paraspeckle-circular RNA TACC3 assembly forms RNA-DNA hybrids to facilitate MASH-related hepatocellular carcinoma growth in an m6A-dependent manner 核内副斑状环状RNA TACC3组装形成RNA- dna杂合体，以m6a依赖的方式促进mash相关肝细胞癌的生长。
IF 24.9 1区 医学 Q1 ONCOLOGY
Cancer Communications
Pub Date : 2025-10-16 DOI: 10.1002/cac2.70061
Jingbo Fu, Yanping Wei, Yun Yang, Xinwei Yang, Tao Ouyang, Xianming Wang, Shuzhen Chen, Zenglin Liu, Yu Su, Jing Fu, Miao Yu, Haihua Qian, Hao Song, Shuo Xu, Ru Zhao, Xue Jiang, Yunfei Huo, Man Zhang, Pinhua Yang, Zhao Yang, Kui Wang, Liang Li, Hongyang Wang
<div> <section> <h3> Background</h3> <p>Metabolic dysfunction-associated steatohepatitis (MASH) is anticipated to become the leading cause of hepatocellular carcinoma (HCC). Accumulating evidence indicates that N6-methyladenosine (m<sup>6</sup>A)-modified circular RNAs (circRNAs) play key roles in tumor malignant progression. However, the precise molecular mechanisms by which circRNAs and their m<sup>6</sup>A modification regulatory networks respond to metabolic reprogramming, such as lipid overload stress, to drive malignant tumor progression in the context of MASH-related HCC remain unclear. This study aimed to investigate the role and regulatory network of m<sup>6</sup>A-modified circRNAs in MASH-related HCC.</p> </section> <section> <h3> Methods</h3> <p>Epitranscriptomic microarray and in situ hybridization assays were used to validate circTACC3 expression in MASH-related HCC specimens. Palmitic acid (PA) and oleic acid (OA) was applied to NAC-organ assembled three-dimensional-organoid and HCC cell lines to imitate pathological lipid overload. The circTACC3-paraspeckle interaction was studied utilizing fluorescence lifetime imaging microscopy-Forster resonance energy transfer. An integrative analysis combining DNA-RNA immunoprecipitation combined with chromatin isolation by RNA purification (DRIP-ChIRP), γH2AX cleavage under target and tagmentation, and high-throughput/resolution chromosome conformation capture sequencing were used to study chromatin remodeling induced by circTACC3-formed RNA-DNA hybrids (R loops) at DNA double-strand break (DSB) loci during lipid overload.</p> </section> <section> <h3> Results</h3> <p>The most prevalent m<sup>6</sup>A-modified circRNA in MASH-related HCC, circTACC3, had a substantial impact on the intracellular lipid accumulation, growth, and environmental adaptive survival of tumor cells. Under lipid overload conditions, circTACC3 interacted directly with non-POU domain-containing octamer-binding protein (NONO/p54<sup>nrb</sup>) to assemble intranuclear paraspeckle. This process was dependent on the m<sup>6</sup>A-modification sites of circTACC3 and facilitated its nuclear retention. Using DRIP-ChIRP-sequencing, we demonstrated that circTACC3-containing paraspeckles were recruited to DSB foci to form R loops (DSB-circTACC3-R loops). We discovered 4 highly enriched motifs of DSB-circTACC3-R loops. DSB-circTACC3-R loops further facilitated the contact and fusion of topologically associated domains (TADs) and selectively activated genes related to the malignant phenotype of MASH-related HCC. Interestingly, circTACC3-R loops exerted positive feedback control over the assembly of circTACC3 paraspeckle and clusteri
背景：代谢功能障碍相关脂肪性肝炎（MASH）有望成为肝细胞癌（HCC）的主要病因。越来越多的证据表明，n6 -甲基腺苷（m6A）修饰的环状rna （circRNAs）在肿瘤恶性进展中起着关键作用。然而，circrna及其m6A修饰调控网络响应代谢重编程（如脂质过载应激）以驱动恶性肿瘤进展的精确分子机制仍不清楚。本研究旨在探讨m6a修饰的环状rna在mash相关HCC中的作用和调控网络。方法：采用表转录组芯片和原位杂交技术验证circTACC3在mash相关HCC标本中的表达。棕榈酸（PA）和油酸（OA）应用于nac -器官组装的三维类器官和HCC细胞系，模拟病理性脂质过载。利用荧光寿命成像显微镜-福斯特共振能量转移技术研究了circtacc3 -副散斑相互作用。采用DNA-RNA免疫沉淀结合RNA纯化分离染色质（DRIP-ChIRP）、靶向和标记下γ - h2ax切割以及高通量/分辨率染色体构象捕获测序的综合分析方法，研究了脂质过载时，circtacc3形成的RNA-DNA杂合体（R环）在DNA双链断裂（DSB）位点诱导的染色质重塑。结果：m6a修饰的circRNA在mash相关HCC中最为普遍，circTACC3对肿瘤细胞的细胞内脂质积累、生长和环境适应性存活具有实质性影响。在脂质过载条件下，circTACC3直接与不含pou结构域的八聚体结合蛋白（NONO/p54nrb）相互作用，组装核内副微粒。这一过程依赖于circTACC3的m6a修饰位点，并促进其核保留。使用drip - chirp测序，我们证明含有circtacc3的副斑点被招募到DSB焦点形成R环（DSB- circtacc3 -R环）。我们发现了DSB-circTACC3-R环的4个高富集基序。DSB-circTACC3-R环进一步促进了拓扑相关结构域（TADs）的接触和融合，并选择性地激活了与mash相关HCC恶性表型相关的基因。有趣的是，circTACC3- r环对circTACC3副斑的组装和tad的聚类具有正反馈控制。结论：m6A修饰依赖性circTACC3-paraspeckle组装导致DSB病灶R环的形成，导致染色质重塑和参与mash相关HCC恶性进展的基因激活。这一过程确定了潜在的治疗靶点。
{"title":"Intranuclear paraspeckle-circular RNA TACC3 assembly forms RNA-DNA hybrids to facilitate MASH-related hepatocellular carcinoma growth in an m6A-dependent manner","authors":"Jingbo Fu,&nbsp;Yanping Wei,&nbsp;Yun Yang,&nbsp;Xinwei Yang,&nbsp;Tao Ouyang,&nbsp;Xianming Wang,&nbsp;Shuzhen Chen,&nbsp;Zenglin Liu,&nbsp;Yu Su,&nbsp;Jing Fu,&nbsp;Miao Yu,&nbsp;Haihua Qian,&nbsp;Hao Song,&nbsp;Shuo Xu,&nbsp;Ru Zhao,&nbsp;Xue Jiang,&nbsp;Yunfei Huo,&nbsp;Man Zhang,&nbsp;Pinhua Yang,&nbsp;Zhao Yang,&nbsp;Kui Wang,&nbsp;Liang Li,&nbsp;Hongyang Wang","doi":"10.1002/cac2.70061","DOIUrl":"10.1002/cac2.70061","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Metabolic dysfunction-associated steatohepatitis (MASH) is anticipated to become the leading cause of hepatocellular carcinoma (HCC). Accumulating evidence indicates that N6-methyladenosine (m&lt;sup&gt;6&lt;/sup&gt;A)-modified circular RNAs (circRNAs) play key roles in tumor malignant progression. However, the precise molecular mechanisms by which circRNAs and their m&lt;sup&gt;6&lt;/sup&gt;A modification regulatory networks respond to metabolic reprogramming, such as lipid overload stress, to drive malignant tumor progression in the context of MASH-related HCC remain unclear. This study aimed to investigate the role and regulatory network of m&lt;sup&gt;6&lt;/sup&gt;A-modified circRNAs in MASH-related HCC.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Epitranscriptomic microarray and in situ hybridization assays were used to validate circTACC3 expression in MASH-related HCC specimens. Palmitic acid (PA) and oleic acid (OA) was applied to NAC-organ assembled three-dimensional-organoid and HCC cell lines to imitate pathological lipid overload. The circTACC3-paraspeckle interaction was studied utilizing fluorescence lifetime imaging microscopy-Forster resonance energy transfer. An integrative analysis combining DNA-RNA immunoprecipitation combined with chromatin isolation by RNA purification (DRIP-ChIRP), γH2AX cleavage under target and tagmentation, and high-throughput/resolution chromosome conformation capture sequencing were used to study chromatin remodeling induced by circTACC3-formed RNA-DNA hybrids (R loops) at DNA double-strand break (DSB) loci during lipid overload.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;The most prevalent m&lt;sup&gt;6&lt;/sup&gt;A-modified circRNA in MASH-related HCC, circTACC3, had a substantial impact on the intracellular lipid accumulation, growth, and environmental adaptive survival of tumor cells. Under lipid overload conditions, circTACC3 interacted directly with non-POU domain-containing octamer-binding protein (NONO/p54&lt;sup&gt;nrb&lt;/sup&gt;) to assemble intranuclear paraspeckle. This process was dependent on the m&lt;sup&gt;6&lt;/sup&gt;A-modification sites of circTACC3 and facilitated its nuclear retention. Using DRIP-ChIRP-sequencing, we demonstrated that circTACC3-containing paraspeckles were recruited to DSB foci to form R loops (DSB-circTACC3-R loops). We discovered 4 highly enriched motifs of DSB-circTACC3-R loops. DSB-circTACC3-R loops further facilitated the contact and fusion of topologically associated domains (TADs) and selectively activated genes related to the malignant phenotype of MASH-related HCC. Interestingly, circTACC3-R loops exerted positive feedback control over the assembly of circTACC3 paraspeckle and clusteri","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 11","pages":"1583-1610"},"PeriodicalIF":24.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70061","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306893","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
RNA m1A methyltransferase TRMT61A promotes colorectal tumorigenesis by enhancing ONECUT2 mRNA stability and is a potential therapeutic target RNA m1A甲基转移酶TRMT61A通过增强ONECUT2 mRNA的稳定性来促进结直肠癌的发生，是一个潜在的治疗靶点。
IF 24.9 1区 医学 Q1 ONCOLOGY
Cancer Communications
Pub Date : 2025-10-16 DOI: 10.1002/cac2.70070
Xiaoting Zhang, Na Qin, Fenfen Ji, Hao Su, Haiyun Shang, Hongyan Chen, Dan Huang, Qing Li, Jing Ren, Weixin Liu, Yifei Wang, Wei Kang, Jiabin Wu, Chi-Chun Wong, Zongwei Cai, Matthew Tak Vai Chan, William Ka Kei Wu, Jun Yu, Huarong Chen

Background

The role of N1-methyladenosine (m1A) in cancer is poorly understood. Here we explored the function of RNA methyltransferase TRNA methyltransferase 61A (TRMT61A) in colorectal cancer (CRC) and its potential as a therapeutic target.

Methods

RNA m1A levels were assessed through liquid chromatography-mass spectrometry. The expression and clinical significance of TRMT61A were investigated across five human CRC cohorts. The function of TRMT61A was elucidated using CRC cell lines, patient-derived organoids, xenografts, and transgenic mouse models. Integrated analyses of m1A-sequencing and RNA-sequencing revealed the underlying mechanisms of TRMT61A. A nanoparticle-based small interfering RNA (siRNA) delivery system and a specific inhibitor were developed to target TRMT61A. The efficacy and safety of targeting TRMT61A were assessed.

Results

Our research revealed a consistent increase in TRMT61A expression and total RNA m1A levels within primary CRCs. High TRMT61A expression was associated with poor prognosis of CRC patients. Through CRISPR/Cas9 screenings, we identified TRMT61A as the most essential gene among m1A regulators. Furthermore, we established that TRMT61A promoted CRC tumorigenesis and progression by enhancing the mRNA stability of critical targets in an m1A-dependent manner. In particular, TRMT61A boosted the mRNA stability of one cut homeobox 2 (ONECUT2), which in turn triggered son of sevenless homolog 1 (SOS1) transcription, leading to the induction of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling in CRC. Notably, our study underscored the safety and substantial anti-CRC effects achievable by inhibiting TRMT61A using nanoparticle-encapsulated siTRMT61A or our newly discovered small molecule compound, pentagalloylglucose.

Conclusions

Our study unveiled the tumor-promoting role of TRMT61A in CRC via the m1A-ONECUT2-SOS1-MAPK/ERK pathway. Targeting TRMT61A showed promise as a therapeutic strategy for treating CRC.

背景：n1 -甲基腺苷（m1A）在癌症中的作用尚不清楚。在这里，我们探讨了RNA甲基转移酶TRNA甲基转移酶61A （TRMT61A）在结直肠癌（CRC）中的功能及其作为治疗靶点的潜力。方法：采用液相色谱-质谱法测定RNA m1A水平。在5个人类CRC队列中研究了TRMT61A的表达及其临床意义。TRMT61A的功能通过CRC细胞系、患者来源的类器官、异种移植和转基因小鼠模型得以阐明。m1a测序和rna测序的综合分析揭示了TRMT61A的潜在机制。开发了基于纳米颗粒的小干扰RNA （siRNA）递送系统和靶向TRMT61A的特异性抑制剂。评估靶向TRMT61A的有效性和安全性。结果：我们的研究揭示了原发性crc中TRMT61A表达和总RNA m1A水平的持续增加。TRMT61A高表达与CRC患者预后不良相关。通过CRISPR/Cas9筛选，我们确定TRMT61A是m1A调控因子中最重要的基因。此外，我们确定TRMT61A通过以m1a依赖的方式增强关键靶点的mRNA稳定性来促进CRC的肿瘤发生和进展。特别是，TRMT61A提高了one cut homobox 2 （ONECUT2）的mRNA稳定性，从而触发了7 - less homolog 1 （SOS1）的转录，导致CRC中丝裂原活化蛋白激酶(MAPK)/细胞外信号调节激酶（ERK）信号的诱导。值得注意的是，我们的研究强调了使用纳米颗粒封装的siTRMT61A或我们新发现的小分子化合物五烯糖基葡萄糖抑制TRMT61A可实现的安全性和实质性的抗crc效果。结论：我们的研究揭示了TRMT61A通过m1A-ONECUT2-SOS1-MAPK/ERK通路在结直肠癌中的促瘤作用。靶向TRMT61A有望成为治疗结直肠癌的治疗策略。
{"title":"RNA m1A methyltransferase TRMT61A promotes colorectal tumorigenesis by enhancing ONECUT2 mRNA stability and is a potential therapeutic target","authors":"Xiaoting Zhang,&nbsp;Na Qin,&nbsp;Fenfen Ji,&nbsp;Hao Su,&nbsp;Haiyun Shang,&nbsp;Hongyan Chen,&nbsp;Dan Huang,&nbsp;Qing Li,&nbsp;Jing Ren,&nbsp;Weixin Liu,&nbsp;Yifei Wang,&nbsp;Wei Kang,&nbsp;Jiabin Wu,&nbsp;Chi-Chun Wong,&nbsp;Zongwei Cai,&nbsp;Matthew Tak Vai Chan,&nbsp;William Ka Kei Wu,&nbsp;Jun Yu,&nbsp;Huarong Chen","doi":"10.1002/cac2.70070","DOIUrl":"10.1002/cac2.70070","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>The role of N1-methyladenosine (m<sup>1</sup>A) in cancer is poorly understood. Here we explored the function of RNA methyltransferase TRNA methyltransferase 61A (TRMT61A) in colorectal cancer (CRC) and its potential as a therapeutic target.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>RNA m<sup>1</sup>A levels were assessed through liquid chromatography-mass spectrometry. The expression and clinical significance of TRMT61A were investigated across five human CRC cohorts. The function of TRMT61A was elucidated using CRC cell lines, patient-derived organoids, xenografts, and transgenic mouse models. Integrated analyses of m<sup>1</sup>A-sequencing and RNA-sequencing revealed the underlying mechanisms of TRMT61A. A nanoparticle-based small interfering RNA (siRNA) delivery system and a specific inhibitor were developed to target TRMT61A. The efficacy and safety of targeting TRMT61A were assessed.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>Our research revealed a consistent increase in TRMT61A expression and total RNA m<sup>1</sup>A levels within primary CRCs. High TRMT61A expression was associated with poor prognosis of CRC patients. Through CRISPR/Cas9 screenings, we identified TRMT61A as the most essential gene among m<sup>1</sup>A regulators. Furthermore, we established that TRMT61A promoted CRC tumorigenesis and progression by enhancing the mRNA stability of critical targets in an m<sup>1</sup>A-dependent manner. In particular, TRMT61A boosted the mRNA stability of one cut homeobox 2 (ONECUT2), which in turn triggered son of sevenless homolog 1 (SOS1) transcription, leading to the induction of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) signaling in CRC. Notably, our study underscored the safety and substantial anti-CRC effects achievable by inhibiting TRMT61A using nanoparticle-encapsulated siTRMT61A or our newly discovered small molecule compound, pentagalloylglucose.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>Our study unveiled the tumor-promoting role of TRMT61A in CRC via the m<sup>1</sup>A-ONECUT2-SOS1-MAPK/ERK pathway. Targeting TRMT61A showed promise as a therapeutic strategy for treating CRC.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 12","pages":"1616-1644"},"PeriodicalIF":24.9,"publicationDate":"2025-10-16","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC12728496/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145306923","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Tumor-infiltrating lymphocyte therapy and the mucosal melanoma treatment landscape 肿瘤浸润性淋巴细胞治疗和粘膜黑色素瘤治疗前景。
IF 24.9 1区 医学 Q1 ONCOLOGY
Cancer Communications
Pub Date : 2025-10-15 DOI: 10.1002/cac2.70069
Jennifer Thomas, Max Julve, James Larkin, Andrew Furness
<p>The systemic treatment of advanced mucosal melanoma (MM) is largely extrapolated from approaches within landmark melanoma clinical trials in which non-cutaneous subtypes are poorly represented. Relevant data are often derived from underpowered subgroup analyses that fail to capture the genetic, microenvironmental and immunological differences of this distinct entity, which, alongside later presentation, likely drive its poorer outcomes relative to cutaneous disease.</p><p>Arising from melanocytes within sun-sheltered (and typically clinically occult) mucosal epithelia, MM genomes are characterized by structural rearrangements and usually lack the ultraviolet light mutational signature associated with high neoantigen burden and sensitivity to immune checkpoint inhibition (ICI) [<span>1</span>]. In a pooled analysis of patients with advanced MM treated in trials of nivolumab with or without ipilimumab, overall response rates (ORR) were 37.1% and 23.3% respectively, compared to 60.4% and 40.9% in cutaneous disease [<span>2</span>]. Canonical <i>BRAF</i> V600 point mutations are rare in MM, and whilst other potentially druggable molecular drivers (most frequently <i>cKIT</i>) have been identified, small trials of targeted agents show limited and short-lived efficacy [<span>3, 4</span>]. Our institution's practice is to offer first-line combination ICI, reserving KIT inhibitors for cKIT-mutated disease in the second line, and best supportive care or cytotoxic chemotherapy thereafter. Given current limitations, clinical trials are preferred at any line where available, and novel data linking meaningful responses with translational insights into MM biology are encouraged.</p><p>Lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy (Figure 1), has received accelerated US Food and Drug Administration approval for advanced melanoma resistant or refractory to anti-programmed cell death protein 1 (PD-1) therapy, based on the single-arm, phase II C-144-01 trial [<span>5, 6</span>]. Kluger et al. [<span>7</span>] recently describe outcomes for the 12 patients with MM within the trial who received lifileucel (amongst 153 treated patients in total), and reported an ORR of 50% with one complete response. This study described a small and highly selected group of patients who not only remained fit for later-line therapy after progression on ICI, but were well enough to undergo surgery followed by intensive non-myeloablative lymphodepleting chemotherapy, with a disease tempo compatible with the required TIL manufacturing process. This selection likely enriched for a subpopulation with less aggressive disease biology than typical for MM. Nevertheless, disease burden at baseline was high, with a median sum of diameters of target lesions being 118.9 mm in the MM subpopulation (101.1 mm across all 153 patients). Despite this, clinically meaningful and durable responses were observed. Median duration of response was not reached at median follow-up of 35.7 months,
晚期粘膜黑色素瘤（MM）的全身治疗主要是从里程碑式黑色素瘤临床试验的方法中推断出来的，其中非皮肤亚型的代表性不足。相关数据通常来自功率不足的亚组分析，无法捕获这一独特实体的遗传、微环境和免疫学差异，这些差异加上较晚的表现，可能导致其相对于皮肤病的预后较差。MM基因组起源于遮阳（通常临床隐匿）粘膜上皮内的黑色素细胞，其特征是结构重排，通常缺乏与高新抗原负担和对免疫检查点抑制（ICI）[1]敏感相关的紫外线突变特征。在nivolumab联合伊匹单抗或不联合伊匹单抗治疗的晚期MM患者的汇总分析中，总体缓解率（ORR）分别为37.1%和23.3%，而皮肤病患者的ORR分别为60.4%和40.9%。典型的BRAF V600点突变在MM中是罕见的，虽然其他潜在的可药物分子驱动因素（最常见的是cKIT）已经确定，但靶向药物的小型试验显示有限且短暂的疗效[3,4]。我们机构的做法是提供一线联合ICI，保留KIT抑制剂用于二线的KIT突变疾病，然后提供最佳支持治疗或细胞毒性化疗。鉴于目前的局限性，临床试验在任何可行的领域都是首选，并且鼓励将有意义的反应与MM生物学的转化见解联系起来的新数据。基于单组II期C-144-01试验，肿瘤浸润淋巴细胞（TIL）疗法Lifileucel（图1）已获得美国食品和药物管理局（fda）加速批准，用于抗程序性细胞死亡蛋白1 （PD-1）治疗的晚期黑色素瘤耐药或难治[5,6]。Kluger等人最近描述了试验中接受lifileucel治疗的12名MM患者（总共153名接受治疗的患者）的结果，并报告了一次完全缓解的ORR为50%。本研究描述了一个小而高度选择的患者组，他们不仅在ICI进展后仍然适合后期治疗，而且足够好，可以接受手术，然后进行强化非清髓性淋巴消耗化疗，疾病节奏与所需的TIL制造过程相匹配。与典型的MM相比，这种选择可能在具有较低侵袭性疾病生物学的亚群中更为丰富。然而，基线时的疾病负担很高，MM亚群中靶病变直径的中位数为118.9 MM（所有153例患者中为101.1 MM）。尽管如此，观察到有临床意义和持久的反应。中位随访时间为35.7个月，未达到中位缓解持续时间，治疗患者的2年总生存率为45.5%。数值上，总体抗pd -1难治性黑色素瘤人群的应答率超过了31.4%的ORR。与皮肤疾病相比，TIL治疗相对于ICI治疗MM更有效，这在生物学上是合理的。迄今为止最大的翻译数据集探索了MM的免疫微环境和ICI耐药的驱动因素，证实了与皮肤病[8]相比，基线时免疫细胞浸润较低。MM微环境具有“更多浸润”转录特征的患者对ICI的反应更频繁（尽管没有达到统计学意义），推断先前存在的抗肿瘤免疫与皮肤疾病一样易发生ICI反应。尽管微环境“浸润程度更高”，但那些没有反应的患者比反应者更有可能具有免疫抑制性癌症相关成纤维细胞和肿瘤相关巨噬细胞的高特征。TIL治疗的基本原理是体外扩增和体内白细胞介素2驱动的激活，否则稀缺的肿瘤反应性淋巴细胞可能抵消免疫抑制的局部特征（包括细胞因子，细胞群和代谢物），以产生有效的抗肿瘤免疫应答[5]。预处理化疗也可能在消耗负调节性免疫细胞中发挥作用。与ICI（单独）相比，该方法的益处可能更大，因为新抗原负担较低，微环境在基线时更具免疫抑制性。这些产生假设的初步数据为将TILs纳入MM一线的试验提供了一些支持，在MM一线，ICI获益的可能性较低。正在进行的随机III期“TILVANCE”试验（NCT05727904）将lifileucel联合派姆单抗（与单独派姆单抗相比）用于先前未治疗的晚期黑色素瘤，包括MM患者，该亚组的结果将特别令人感兴趣。 其他在肿瘤微环境中招募/保留和激活免疫效应细胞的策略在MM中也很有吸引力，但疗效数据仍然受到其低发病率和临床试验代表性的限制。癌睾丸抗原PRAME经常在MM[9]中表达，但PRAME定向的双特异性T细胞参与器的试验显示，单独或与抗pd -1 ICI联合治疗皮肤黑色素瘤的效果良好，排除了MM （NCT06112314, NCT04262466）。在一项自体prame定向T细胞受体T细胞治疗的I期研究中，两名MM患者中的一名经历了深刻而持久的反应，值得进一步探索。在免疫治疗之外，有希望的合理方法包括通过复发性结构重排靶向与肿瘤发生有关的途径。除了激活cKIT突变（可能发生在规范外显子11l576位点[4]之外），67mm的全基因组测序还发现了影响丝裂原活化蛋白激酶和WNT信号通路的其他成分以及端粒长度[1]调节的结构变异。值得注意的是，70%的队列具有与细胞周期蛋白依赖性激酶（CDK）4/6抑制反应相关的突变。在临床前研究中，Dalpiciclib抑制了患者来源的cdk4扩增头颈部MM异种移植模型的生长，但在该人群中进行的一项小型（n = 17）、非随机、开放标签的II期试验中，ORR为6%。尽管如此，报道的81%的疾病控制率、广泛的可获得性和已建立的耐受性使得CDK4/6抑制剂在该领域的进一步评估是合理的。前瞻性临床数据显然是必需的，但对于罕见的、临床和生物学异质性的癌症，如MM，这将始终是一个挑战，特别是当在行业资助的研究中纳入这组患者（既往预后不良和反应率低）的兴趣可能很低时。正在进行的集体国际转化努力被敦促更好地了解这一实体的生物学和脆弱性，从而优先考虑和指导临床研究途径。Jennifer Thomas博士和Max Julve博士撰写并编辑了手稿。安德鲁·弗内斯博士和詹姆斯·拉金教授提供了专家意见和评论。m。j。声明没有利益冲突。J.L.宣布：酬金（卫材、诺华、Incyte、默克、touchIME、touchEXPERTS、辉瑞、皇家医师学院、剑桥医疗保健研究、皇家全科医师学院、VJOncology、Agence Unik、BMS、imatics、insight和GCO）；咨询公司（iOnctura, Apple Tree, Merck， BMS, Eisai, Debipharm, Incyte, Pfizer, Novartis， MSD）。演讲费：Pierre Fabre、BMS、Ipsen、Roche、EUSA Pharma、Novartis、Aptitude、AstraZeneca、GSK、Eisai、Calithera、Ultimovacs、Seagen、Merck、eCancer、Inselgruppe、Pfizer、Goldman Sachs、MSD、Regional British Society of Gastroenterology、Agence Unik)；机构研究支持（BMS、MSD、诺华、辉瑞、Achilles Therapeutics、罗氏、Nektar Therapeutics、Covance、Immunocore、pharmacyics和Aveo）；和资助（Achilles、BMS、MSD、Nektar、Novartis、Pfizer、Roche、Immunocore、Aveo和pharmacyics）。A.J.S.F.宣布：演讲者局和教育活动（BMS、卫材、Ipsen、默克和辉瑞）；支持参加会议和/或出差（Achilles Therapeutics, Adaptimmune， E
{"title":"Tumor-infiltrating lymphocyte therapy and the mucosal melanoma treatment landscape","authors":"Jennifer Thomas,&nbsp;Max Julve,&nbsp;James Larkin,&nbsp;Andrew Furness","doi":"10.1002/cac2.70069","DOIUrl":"10.1002/cac2.70069","url":null,"abstract":"&lt;p&gt;The systemic treatment of advanced mucosal melanoma (MM) is largely extrapolated from approaches within landmark melanoma clinical trials in which non-cutaneous subtypes are poorly represented. Relevant data are often derived from underpowered subgroup analyses that fail to capture the genetic, microenvironmental and immunological differences of this distinct entity, which, alongside later presentation, likely drive its poorer outcomes relative to cutaneous disease.&lt;/p&gt;&lt;p&gt;Arising from melanocytes within sun-sheltered (and typically clinically occult) mucosal epithelia, MM genomes are characterized by structural rearrangements and usually lack the ultraviolet light mutational signature associated with high neoantigen burden and sensitivity to immune checkpoint inhibition (ICI) [&lt;span&gt;1&lt;/span&gt;]. In a pooled analysis of patients with advanced MM treated in trials of nivolumab with or without ipilimumab, overall response rates (ORR) were 37.1% and 23.3% respectively, compared to 60.4% and 40.9% in cutaneous disease [&lt;span&gt;2&lt;/span&gt;]. Canonical &lt;i&gt;BRAF&lt;/i&gt; V600 point mutations are rare in MM, and whilst other potentially druggable molecular drivers (most frequently &lt;i&gt;cKIT&lt;/i&gt;) have been identified, small trials of targeted agents show limited and short-lived efficacy [&lt;span&gt;3, 4&lt;/span&gt;]. Our institution's practice is to offer first-line combination ICI, reserving KIT inhibitors for cKIT-mutated disease in the second line, and best supportive care or cytotoxic chemotherapy thereafter. Given current limitations, clinical trials are preferred at any line where available, and novel data linking meaningful responses with translational insights into MM biology are encouraged.&lt;/p&gt;&lt;p&gt;Lifileucel, a tumor-infiltrating lymphocyte (TIL) therapy (Figure 1), has received accelerated US Food and Drug Administration approval for advanced melanoma resistant or refractory to anti-programmed cell death protein 1 (PD-1) therapy, based on the single-arm, phase II C-144-01 trial [&lt;span&gt;5, 6&lt;/span&gt;]. Kluger et al. [&lt;span&gt;7&lt;/span&gt;] recently describe outcomes for the 12 patients with MM within the trial who received lifileucel (amongst 153 treated patients in total), and reported an ORR of 50% with one complete response. This study described a small and highly selected group of patients who not only remained fit for later-line therapy after progression on ICI, but were well enough to undergo surgery followed by intensive non-myeloablative lymphodepleting chemotherapy, with a disease tempo compatible with the required TIL manufacturing process. This selection likely enriched for a subpopulation with less aggressive disease biology than typical for MM. Nevertheless, disease burden at baseline was high, with a median sum of diameters of target lesions being 118.9 mm in the MM subpopulation (101.1 mm across all 153 patients). Despite this, clinically meaningful and durable responses were observed. Median duration of response was not reached at median follow-up of 35.7 months, ","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 11","pages":"1579-1582"},"PeriodicalIF":24.9,"publicationDate":"2025-10-15","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70069","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145291240","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
CD24 is a promising immunotherapeutic target for enhancing efficacy of third-generation EGFR-TKIs on EGFR-mutated lung cancer CD24是提高第三代EGFR-TKIs治疗egfr突变肺癌疗效的有希望的免疫治疗靶点。
IF 24.9 1区 医学 Q1 ONCOLOGY
Cancer Communications
Pub Date : 2025-10-13 DOI: 10.1002/cac2.70068
Jiaqi Liang, Guoshu Bi, Xiaolong Huang, Zhijie Xu, Yiwei Huang, Yunyi Bian, Guangyao Shan, Wei Guo, Yuanliang Yan, Qihai Sui, Xiaodong Yang, Zhencong Chen, Tao Lu, Huan Zhang, Qun Wang, Wei Jiang, Cheng Zhan

Background

Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show initial efficacy in EGFR-mutated lung cancer, but residual disease persists. This study aimed to investigate cluster of differentiation 24 (CD24) as a translational immunotherapeutic target for enhancing third-generation EGFR-TKI efficacy.

Methods

We conducted RNA-sequencing (RNA-seq) on drug-responsive, drug-tolerant persister, and drug-resistant cells to identify therapeutic targets to pair with EGFR-TKIs. For validation, we integrated single-cell RNA-seq data from 29 lung cancer specimens and used single-nucleus RNA-seq and immunohistochemistry on clinical residual tumor samples following TKI therapy (TKI-residual). With CRISPR/Cas9, we studied the effect of CD24 on proliferation and phagocytic clearance during EGFR-TKI treatment. We tested CD24 knockout or ATG-031 (a first-in-class CD24 antibody) with EGFR-TKIs in vitro, xenografts, and spontaneous lung cancer models. To explore mechanisms, we used DNA affinity precipitation, chromatin immunoprecipitation sequencing, and luciferase assays to identify transcription factors regulating CD24. Co-immunoprecipitation combined with mass spectrometry and phosphoproteomics were used to study YIN-YANG-1 (YY1) S247 phosphorylation's expression and function, while kinase inhibitors assessed upstream phosphorylation of YY1 S247 and its regulation of CD24.

Results

CD24 expression rose in drug-responsive, -resistant, and -tolerant lung cancer cells and post-EGFR-TKI treatment clinical specimens. This elevation promoted cell proliferation and shielded tumor cells from macrophage-mediated phagocytosis. Genetic depletion of CD24 or treatment with ATG-031 significantly enhanced phagocytosis and tumor eradication in vitro, in xenografts, and in mice harboring EGFRL858R·T790M-driven spontaneous lung tumors. Furthermore, we revealed that YY1 S247 phosphorylation was responsible for the upregulation of CD24 upon EGFR-TKI treatment, facilitating YY1 dimerization and the formation of promoter-enhancer loops that regulate CD24 expression.

Conclusions

CD24 is a promising target in EGFR-mutated lung cancers, potentially enhancing efficacy of third-generation EGFR-TKIs.

背景：第三代表皮生长因子受体（EGFR）酪氨酸激酶抑制剂（TKIs）在EGFR突变的肺癌中显示出初步疗效，但残留疾病仍然存在。本研究旨在探讨CD24作为提高第三代EGFR-TKI疗效的转化性免疫治疗靶点。方法：我们对药物反应性、耐药持久性和耐药细胞进行rna测序（RNA-seq），以确定与EGFR-TKIs配对的治疗靶点。为了验证，我们整合了来自29例肺癌标本的单细胞RNA-seq数据，并对TKI治疗后的临床残留肿瘤样本（TKI-residual）进行了单核RNA-seq和免疫组织化学分析。利用CRISPR/Cas9，我们研究了在EGFR-TKI治疗期间CD24对细胞增殖和吞噬清除的影响。我们在体外、异种移植和自发性肺癌模型中对EGFR-TKIs进行了CD24敲除或ATG-031（一种一流的CD24抗体）测试。为了探索机制，我们使用DNA亲和沉淀、染色质免疫沉淀测序和荧光素酶测定来鉴定调节CD24的转录因子。采用免疫共沉淀法结合质谱法和磷酸化蛋白质组学研究了YIN-YANG-1 (YY1) S247磷酸化的表达和功能，激酶抑制剂评估了YY1 S247上游磷酸化及其对CD24的调控。结果：CD24在耐药、耐药、耐药肺癌细胞及egfr - tki治疗后临床标本中表达升高。这种升高促进了细胞增殖，并保护肿瘤细胞免受巨噬细胞介导的吞噬作用。CD24基因缺失或ATG-031治疗可显著增强体外、异种移植物和携带EGFRL858R·t790m驱动的自发性肺肿瘤的小鼠的吞噬和肿瘤根除。此外，我们发现YY1 S247磷酸化是EGFR-TKI处理时CD24上调的原因，促进YY1二聚化和形成调节CD24表达的启动子-增强子环。结论：CD24是egfr突变肺癌的一个有希望的靶点，可能增强第三代EGFR-TKIs的疗效。
{"title":"CD24 is a promising immunotherapeutic target for enhancing efficacy of third-generation EGFR-TKIs on EGFR-mutated lung cancer","authors":"Jiaqi Liang,&nbsp;Guoshu Bi,&nbsp;Xiaolong Huang,&nbsp;Zhijie Xu,&nbsp;Yiwei Huang,&nbsp;Yunyi Bian,&nbsp;Guangyao Shan,&nbsp;Wei Guo,&nbsp;Yuanliang Yan,&nbsp;Qihai Sui,&nbsp;Xiaodong Yang,&nbsp;Zhencong Chen,&nbsp;Tao Lu,&nbsp;Huan Zhang,&nbsp;Qun Wang,&nbsp;Wei Jiang,&nbsp;Cheng Zhan","doi":"10.1002/cac2.70068","DOIUrl":"10.1002/cac2.70068","url":null,"abstract":"<div>\u0000 \u0000 \u0000 <section>\u0000 \u0000 <h3> Background</h3>\u0000 \u0000 <p>Third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) show initial efficacy in EGFR-mutated lung cancer, but residual disease persists. This study aimed to investigate cluster of differentiation 24 (CD24) as a translational immunotherapeutic target for enhancing third-generation EGFR-TKI efficacy.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Methods</h3>\u0000 \u0000 <p>We conducted RNA-sequencing (RNA-seq) on drug-responsive, drug-tolerant persister, and drug-resistant cells to identify therapeutic targets to pair with EGFR-TKIs. For validation, we integrated single-cell RNA-seq data from 29 lung cancer specimens and used single-nucleus RNA-seq and immunohistochemistry on clinical residual tumor samples following TKI therapy (TKI-residual). With CRISPR/Cas9, we studied the effect of CD24 on proliferation and phagocytic clearance during EGFR-TKI treatment. We tested CD24 knockout or ATG-031 (a first-in-class CD24 antibody) with EGFR-TKIs in vitro, xenografts, and spontaneous lung cancer models. To explore mechanisms, we used DNA affinity precipitation, chromatin immunoprecipitation sequencing, and luciferase assays to identify transcription factors regulating CD24. Co-immunoprecipitation combined with mass spectrometry and phosphoproteomics were used to study YIN-YANG-1 (YY1) S247 phosphorylation's expression and function, while kinase inhibitors assessed upstream phosphorylation of YY1 S247 and its regulation of CD24.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Results</h3>\u0000 \u0000 <p>CD24 expression rose in drug-responsive, -resistant, and -tolerant lung cancer cells and post-EGFR-TKI treatment clinical specimens. This elevation promoted cell proliferation and shielded tumor cells from macrophage-mediated phagocytosis. Genetic depletion of CD24 or treatment with ATG-031 significantly enhanced phagocytosis and tumor eradication in vitro, in xenografts, and in mice harboring EGFRL858R·T790M-driven spontaneous lung tumors. Furthermore, we revealed that YY1 S247 phosphorylation was responsible for the upregulation of CD24 upon EGFR-TKI treatment, facilitating YY1 dimerization and the formation of promoter-enhancer loops that regulate CD24 expression.</p>\u0000 </section>\u0000 \u0000 <section>\u0000 \u0000 <h3> Conclusions</h3>\u0000 \u0000 <p>CD24 is a promising target in EGFR-mutated lung cancers, potentially enhancing efficacy of third-generation EGFR-TKIs.</p>\u0000 </section>\u0000 </div>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 11","pages":"1547-1578"},"PeriodicalIF":24.9,"publicationDate":"2025-10-13","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70068","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145285759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Breaking barriers: The cGAS-STING pathway as a novel frontier in cancer immunotherapy 突破障碍：cGAS-STING通路作为癌症免疫治疗的新前沿。
IF 24.9 1区 医学 Q1 ONCOLOGY
Cancer Communications
Pub Date : 2025-10-12 DOI: 10.1002/cac2.70067
Yuheng Yan, Ximin Tan, Bin Song, Ming Yi, Qian Chu, Kongming Wu

Since its discovery, the cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon gene (STING) signaling pathway has been considered a pivotal component of innate immunity and a promising target for cancer immunotherapy. Beyond its canonical role in pathogen defense, accumulating evidence has demonstrated that the cGAS-STING pathway critically regulates diverse cellular processes, including cellular senescence, autophagy, cell death, and tumor immunosurveillance; therefore, dysregulation of this pathway correlates with the pathogenesis and progression of various human diseases, ranging from autoimmune and inflammatory disorders to cancer. Herein, we reviewed the regulatory mechanisms and cellular functions of the cGAS-STING pathway, highlighting its essential role in maintaining immune homeostasis. We systematically discussed the dual roles of the cGAS-STING pathway in cancer immunity, in which it triggers both antitumor and immunosuppressive effects. Finally, we summarized the recent advances and challenges in therapeutic strategies targeting the cGAS-STING pathway and discussed the next generation of therapies, including nanomaterials, antibody-drug conjugates, engineered bacteria, alternative strategies, optogenetic approaches, and combination strategies. We hope that our efforts will advance the understanding of the fundamental principles of innate immune recognition and response, and provide novel directions for improving the clinical outcomes of cGAS-STING-targeted therapies.

自发现以来，干扰素基因（STING）信号通路的环GMP-AMP合成酶（cGAS）刺激物一直被认为是先天免疫的关键组成部分，也是癌症免疫治疗的一个有希望的靶点。除了在病原体防御中的典型作用外，越来越多的证据表明，cGAS-STING通路对多种细胞过程具有关键调控作用，包括细胞衰老、自噬、细胞死亡和肿瘤免疫监视；因此，该通路的失调与各种人类疾病的发病和进展有关，包括自身免疫性和炎症性疾病到癌症。本文综述了cGAS-STING通路的调控机制和细胞功能，强调了其在维持免疫稳态中的重要作用。我们系统地讨论了cGAS-STING通路在肿瘤免疫中的双重作用，它触发抗肿瘤和免疫抑制作用。最后，我们总结了针对cGAS-STING通路的治疗策略的最新进展和挑战，并讨论了下一代治疗策略，包括纳米材料、抗体-药物偶联物、工程细菌、替代策略、光遗传方法和联合策略。我们希望我们的工作能够促进对先天免疫识别和应答基本原理的理解，并为提高cgas - sting靶向治疗的临床效果提供新的方向。
{"title":"Breaking barriers: The cGAS-STING pathway as a novel frontier in cancer immunotherapy","authors":"Yuheng Yan,&nbsp;Ximin Tan,&nbsp;Bin Song,&nbsp;Ming Yi,&nbsp;Qian Chu,&nbsp;Kongming Wu","doi":"10.1002/cac2.70067","DOIUrl":"10.1002/cac2.70067","url":null,"abstract":"<p>Since its discovery, the cyclic GMP-AMP synthase (cGAS)-stimulator of the interferon gene (STING) signaling pathway has been considered a pivotal component of innate immunity and a promising target for cancer immunotherapy. Beyond its canonical role in pathogen defense, accumulating evidence has demonstrated that the cGAS-STING pathway critically regulates diverse cellular processes, including cellular senescence, autophagy, cell death, and tumor immunosurveillance; therefore, dysregulation of this pathway correlates with the pathogenesis and progression of various human diseases, ranging from autoimmune and inflammatory disorders to cancer. Herein, we reviewed the regulatory mechanisms and cellular functions of the cGAS-STING pathway, highlighting its essential role in maintaining immune homeostasis. We systematically discussed the dual roles of the cGAS-STING pathway in cancer immunity, in which it triggers both antitumor and immunosuppressive effects. Finally, we summarized the recent advances and challenges in therapeutic strategies targeting the cGAS-STING pathway and discussed the next generation of therapies, including nanomaterials, antibody-drug conjugates, engineered bacteria, alternative strategies, optogenetic approaches, and combination strategies. We hope that our efforts will advance the understanding of the fundamental principles of innate immune recognition and response, and provide novel directions for improving the clinical outcomes of cGAS-STING-targeted therapies.</p>","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 11","pages":"1513-1546"},"PeriodicalIF":24.9,"publicationDate":"2025-10-12","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70067","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145278981","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Efficacy and safety of glecirasib in solid tumors with KRAS G12C mutation: A pooled analysis of two phase I/II trials glecirasib治疗KRAS G12C突变实体瘤的疗效和安全性：两项I/II期试验的汇总分析
IF 24.9 1区 医学 Q1 ONCOLOGY
Cancer Communications
Pub Date : 2025-10-02 DOI: 10.1002/cac2.70056
Jian Li, Ting Deng, Yanhong Gu, Antonio Calles Blanco, Zhihua Li, Chunmei Bai, Lin Wu, Jing Huang, Xingya Li, Yu Yao, Zhengbo Song, Yongsheng Li, Lian Liu, Ligang Xing, Wenming Wu, Julia Martínez-Pérez, Ayala Hubert, Jon Zugazagoitia, Jian Zhang, Yongsheng Wang, Yanqiu Zhao, Guilan Wen, Guohao Xia, Diansheng Zhong, Xueqin Chen, Kuirong Jiang, Andrea Wang-Gillam, Yuli Ding, Sumei Liu, Zhiyue Rao, Xinghu Liu, Lin Shen
<div> <section> <h3> Background</h3> <p>Glecirasib, an inhibitor of Kirsten rat sarcoma viral oncogene homolog glycine-to-cysteine substitution at codon 12 (<i>KRAS</i> G12C), has exhibited clinical activity in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). Here, we investigated the efficacy and safety of glecirasib in patients with pancreatic ductal adenocarcinoma (PDAC) and other solid tumors (excluding NSCLC and CRC) that rarely harbor the <i>KRAS</i> G12C mutation but for which effective treatment options remain limited.</p> </section> <section> <h3> Methods</h3> <p>We conducted and analyzed two open-label, phase I/II trials in adult patients with <i>KRAS</i> G12C mutant solid tumors, in which glecirasib was administered orally. The two trials had similar eligibility criteria and endpoints but differed in the regions of patient recruitment. We performed a pooled analysis of all patients, excluding NSCLC and CRC, from both trials. The primary endpoint in the pooled population was objective response rate (ORR). Efficacy and safety were assessed in patients who received at least one dose of glecirasib.</p> </section> <section> <h3> Results</h3> <p>As of June 30, 2024, the pooled analysis included 54 patients who were treated with glecirasib: 32 PDACs, 8 biliary tract cancers (BTCs), 4 small intestinal cancers, 3 gastric cancers, 2 appendiceal cancers, and 5 other tumors. At baseline, 24 received ≥ two prior lines of systemic therapy. Of the 53 efficacy-evaluable patients, the confirmed ORR was 50.9% (95% confidence interval [CI], 36.8%-64.9%), with an ORR of 46.9% (95% CI, 29.1%-65.3%) in PDAC patients. Among other solid tumors, ORR was 71.4% (5/7) in BTC, 100% (4/4) in small intestinal cancer, and 66.7% (2/3) in gastric cancer. Median progression-free survival and median overall survival were 6.9 and 10.8 months, respectively, in the overall population, and 5.5 and 10.8 months, respectively, in patients with PDAC. Treatment-related adverse events (TRAEs) of any grade occurred in 94.4% patients, with grade ≥ 3 TRAEs in 27.8%. No fatal TRAEs or TRAEs leading to treatment discontinuation occurred.</p> </section> <section> <h3> Conclusions</h3> <p>Glecirasib showed promising efficacy and was well tolerated in patients with PDAC and other advanced solid tumors (beyond NSCLC and CRC), warranting further expedited clinical development in this patient population.</p> </section> <section> <h3> Trial registration</h3> <p>ClinicalTrials.gov
背景：Glecirasib是Kirsten大鼠肉瘤病毒癌基因同源基因甘氨酸-半胱氨酸替换密码子12 （KRAS G12C）的抑制剂，已在非小细胞肺癌（NSCLC）和结直肠癌（CRC）中显示出临床活性。在这里，我们研究了glecirasib在胰腺导管腺癌（PDAC）和其他实体肿瘤（不包括NSCLC和CRC）患者中的疗效和安全性，这些肿瘤很少携带KRAS G12C突变，但有效的治疗选择仍然有限。方法：我们对KRAS G12C突变实体瘤成年患者进行了两项开放标签I/II期试验，其中口服格拉西布。这两项试验具有相似的资格标准和终点，但在患者招募地区不同。我们对两项试验的所有患者进行了汇总分析，不包括NSCLC和CRC。合并人群的主要终点是客观缓解率（ORR）。在接受至少一剂格拉西布的患者中评估了疗效和安全性。结果：截至2024年6月30日，汇总分析纳入54例接受glecirasib治疗的患者：32例pdac， 8例胆道癌（btc）， 4例小肠癌，3例胃癌，2例阑尾癌和5例其他肿瘤。在基线时，24人接受了≥两条既往的全身治疗。在53例可评估疗效的患者中，确诊的ORR为50.9%(95%可信区间[CI]， 36.8%-64.9%)， PDAC患者的ORR为46.9% （95% CI, 29.1%-65.3%）。在其他实体肿瘤中，BTC的ORR为71.4%(5/7)，小肠肿瘤为100%(4/4)，胃癌为66.7%（2/3）。总体人群的中位无进展生存期和中位总生存期分别为6.9和10.8个月，PDAC患者的中位无进展生存期和中位总生存期分别为5.5和10.8个月。94.4%的患者发生了任何级别的治疗相关不良事件（TRAEs）， 27.8%的患者发生了≥3级的TRAEs。没有发生致命的trae或导致治疗中断的trae。结论：Glecirasib在PDAC和其他晚期实体肿瘤（非小细胞肺癌和结直肠癌）患者中显示出良好的疗效和耐受性，需要进一步加快该患者群体的临床开发。试验注册：ClinicalTrials.gov标识符：NCT05009329和NCT05002270。
{"title":"Efficacy and safety of glecirasib in solid tumors with KRAS G12C mutation: A pooled analysis of two phase I/II trials","authors":"Jian Li,&nbsp;Ting Deng,&nbsp;Yanhong Gu,&nbsp;Antonio Calles Blanco,&nbsp;Zhihua Li,&nbsp;Chunmei Bai,&nbsp;Lin Wu,&nbsp;Jing Huang,&nbsp;Xingya Li,&nbsp;Yu Yao,&nbsp;Zhengbo Song,&nbsp;Yongsheng Li,&nbsp;Lian Liu,&nbsp;Ligang Xing,&nbsp;Wenming Wu,&nbsp;Julia Martínez-Pérez,&nbsp;Ayala Hubert,&nbsp;Jon Zugazagoitia,&nbsp;Jian Zhang,&nbsp;Yongsheng Wang,&nbsp;Yanqiu Zhao,&nbsp;Guilan Wen,&nbsp;Guohao Xia,&nbsp;Diansheng Zhong,&nbsp;Xueqin Chen,&nbsp;Kuirong Jiang,&nbsp;Andrea Wang-Gillam,&nbsp;Yuli Ding,&nbsp;Sumei Liu,&nbsp;Zhiyue Rao,&nbsp;Xinghu Liu,&nbsp;Lin Shen","doi":"10.1002/cac2.70056","DOIUrl":"10.1002/cac2.70056","url":null,"abstract":"&lt;div&gt;\u0000 \u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Background&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Glecirasib, an inhibitor of Kirsten rat sarcoma viral oncogene homolog glycine-to-cysteine substitution at codon 12 (&lt;i&gt;KRAS&lt;/i&gt; G12C), has exhibited clinical activity in non-small-cell lung cancer (NSCLC) and colorectal cancer (CRC). Here, we investigated the efficacy and safety of glecirasib in patients with pancreatic ductal adenocarcinoma (PDAC) and other solid tumors (excluding NSCLC and CRC) that rarely harbor the &lt;i&gt;KRAS&lt;/i&gt; G12C mutation but for which effective treatment options remain limited.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Methods&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;We conducted and analyzed two open-label, phase I/II trials in adult patients with &lt;i&gt;KRAS&lt;/i&gt; G12C mutant solid tumors, in which glecirasib was administered orally. The two trials had similar eligibility criteria and endpoints but differed in the regions of patient recruitment. We performed a pooled analysis of all patients, excluding NSCLC and CRC, from both trials. The primary endpoint in the pooled population was objective response rate (ORR). Efficacy and safety were assessed in patients who received at least one dose of glecirasib.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Results&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;As of June 30, 2024, the pooled analysis included 54 patients who were treated with glecirasib: 32 PDACs, 8 biliary tract cancers (BTCs), 4 small intestinal cancers, 3 gastric cancers, 2 appendiceal cancers, and 5 other tumors. At baseline, 24 received ≥ two prior lines of systemic therapy. Of the 53 efficacy-evaluable patients, the confirmed ORR was 50.9% (95% confidence interval [CI], 36.8%-64.9%), with an ORR of 46.9% (95% CI, 29.1%-65.3%) in PDAC patients. Among other solid tumors, ORR was 71.4% (5/7) in BTC, 100% (4/4) in small intestinal cancer, and 66.7% (2/3) in gastric cancer. Median progression-free survival and median overall survival were 6.9 and 10.8 months, respectively, in the overall population, and 5.5 and 10.8 months, respectively, in patients with PDAC. Treatment-related adverse events (TRAEs) of any grade occurred in 94.4% patients, with grade ≥ 3 TRAEs in 27.8%. No fatal TRAEs or TRAEs leading to treatment discontinuation occurred.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Conclusions&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;Glecirasib showed promising efficacy and was well tolerated in patients with PDAC and other advanced solid tumors (beyond NSCLC and CRC), warranting further expedited clinical development in this patient population.&lt;/p&gt;\u0000 &lt;/section&gt;\u0000 \u0000 &lt;section&gt;\u0000 \u0000 &lt;h3&gt; Trial registration&lt;/h3&gt;\u0000 \u0000 &lt;p&gt;ClinicalTrials.gov","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 11","pages":"1500-1512"},"PeriodicalIF":24.9,"publicationDate":"2025-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70056","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145211883","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Diagnostic performance of a circulating tumor DNA-based blood test compared to fecal immunochemical test in colorectal cancer screening 循环肿瘤dna血液检测与粪便免疫化学检测在结直肠癌筛查中的诊断价值
IF 24.9 1区 医学 Q1 ONCOLOGY
Cancer Communications
Pub Date : 2025-09-30 DOI: 10.1002/cac2.70066
Hermann Brenner, Teresa Seum, Megha Bhardwaj, Michael Hoffmeister

Screening for colorectal cancer (CRC) has the potential to strongly reduce incidence and mortality of this common cancer [1, 2]. While fecal tests have long been established as non-invasive CRC screening tests, an intensive search for blood-based tests, which have been claimed to be easier to integrate into routine medical practice, is underway [3, 4]. Most recently, clinical validation of a circulating tumor DNA-based blood test for the detection of patterns of CpG (cytosine followed by guanine) dinucleotide methylation has been reported from the PREEMPT CRC study, a large, United States (US) based screening study including 27,010 participants of screening colonoscopy [4]. The study was sponsored by the manufacturer and reported with limited details about the laboratory analyses. With a sensitivity of 79.2% (95% confidence interval [CI], 68.4%-86.9%) for CRC detection and a specificity of 91.5% (95% CI, 91.2%-91.9%) for advanced colorectal neoplasia, the test met the pre-specified acceptance criteria, but the sensitivity for detecting advanced precancerous lesions (APCL) was low (12.5%). We aimed to compare the reported diagnostic performance of this blood-based test with that of the fecal immunochemical test (FIT), the best established and globally most widely used non-invasive CRC test [5], in a large population of screening colonoscopy participants from Germany.

Our analyses are based on data from the ongoing BLITZ study, whose design has been reported in detail elsewhere [6]. Briefly, participants undergoing screening colonoscopies were recruited in gastroenterology practices in Southern Germany and asked to complete a short questionnaire and provide a fecal sample prior to bowel preparation for the evaluation of non-invasive CRC screening tests. Participants for this analysis were selected from 10,061 participants recruited between 2008 and 2020 for whom the same quantitative FIT (FOB Gold, Sentinel Diagnostics, Milano, Italy) was performed. The diagnostic performance characteristics of the FOB Gold assay were determined at the manufacturer-recommended cutoff of 17.0 µg hemoglobin per gram of feces. To ensure comparability, we matched the inclusion and exclusion criteria as closely as possible to those of the PREEMPT CRC study, as outlined in the flow diagram in Supplementary Figure S1. We compared the sensitivity for detecting CRC (separately for any stage and stages I-III), advanced precancerous lesions (APCL) and any advanced neoplasia (CRC or APCL), and the specificity of the blood test reported from the PREEMPT CRC study to the corresponding metrics for the FIT in the BLITZ study. APCL included in situ or high-grade dysplasia, adenoma with villous growth pattern (≥ 25%), adenoma ≥ 1.0 cm, sessile serrated lesion ≥ 1.0 cm, and traditional serrated adenoma of any size. Differences were tested for statistical significance by two-sided chi-square tests at an alpha le

结直肠癌（CRC）筛查有可能大大降低这种常见癌症的发病率和死亡率[1,2]。虽然粪便检查长期以来一直被认为是一种非侵入性的CRC筛查方法，但人们正在大力寻找据称更容易融入常规医疗实践的基于血液的检查[3,4]。最近，PREEMPT CRC研究报告了循环肿瘤dna血液检测CpG（胞嘧啶和鸟嘌呤）二核苷酸甲基化模式的临床验证。PREEMPT CRC研究是一项大型美国筛查研究，包括27,010名结肠镜筛查参与者。这项研究是由制造商赞助的，报告中关于实验室分析的细节有限。检测结直肠癌的灵敏度为79.2%(95%置信区间[CI]， 68.4% ~ 86.9%)，检测晚期结直肠癌的特异性为91.5% (95% CI, 91.2% ~ 91.9%)，符合预先规定的接受标准，但检测晚期癌前病变（APCL）的灵敏度较低（12.5%）。我们的目的是在德国的大量结肠镜筛查参与者中，比较这种基于血液的测试与粪便免疫化学测试（FIT）的诊断性能，FIT是最成熟且全球最广泛使用的非侵入性CRC测试[5]。我们的分析基于正在进行的闪电战研究的数据，其设计已在其他地方详细报道。简而言之，在德国南部的胃肠病学实践中招募了接受筛查结肠镜检查的参与者，并要求他们完成一份简短的问卷调查，并在肠道准备之前提供粪便样本，以评估非侵入性CRC筛查试验。本分析的参与者是从2008年至2020年间招募的10,061名参与者中选择的，对他们进行了相同的定量FIT （FOB Gold, Sentinel Diagnostics, Milano, Italy）。FOB金法的诊断性能特征是在制造商推荐的每克粪便17.0µg血红蛋白的临界值下确定的。为了确保可比性，我们尽可能将纳入和排除标准与PREEMPT CRC研究的标准相匹配，如补充图S1中的流程图所示。我们比较了检测CRC（单独检测任何阶段和I-III期）、晚期癌前病变（APCL）和任何晚期肿瘤（CRC或APCL）的敏感性，以及PREEMPT CRC研究报告的血液检测的特异性与BLITZ研究中FIT的相应指标。APCL包括原位或高度不典型增生，腺瘤伴绒毛生长模式（≥25%），腺瘤≥1.0 cm，无柄锯齿状病变≥1.0 cm，以及任何大小的传统锯齿状腺瘤。采用双侧卡方检验，α水平为0.05。除了对整个研究人群进行分析外，我们还确定了按性别和年龄定义的亚组检测任何晚期肿瘤的敏感性和特异性。采用R版本4.4.0进行分析。PREEMPT CRC和BLITZ研究人群的主要特征见补充表S1。男性在BLITZ中的比例（49.3%）高于PREEMPT CRC （44.2%, P &lt; 0.001）。在BLITZ研究中，CRC和APCL的患病率也显著更高（P &lt; 0.001）（0.8%和14.4%对0.3%和9.5%），其中老年参与者的比例更高。BLITZ中FIT对APCL的敏感性（23.7%对12.5%）和任何晚期肿瘤（27.1%对14.3%）以及特异性（93.2%对91.5%）都明显高于PREEMPT CRC的血液检查（P均为0.001；表1）。FIT检测结直肠癌的敏感性也高于血液检查（89.8%比79.2%），但差异无统计学意义。在亚组特异性分析中，在男性和女性以及55-64岁和≥65岁年龄组中，BLITZ中FIT检测任何晚期肿瘤的敏感性和特异性始终高于PREEMPT CRC的血液检查（男性特异性的P值= 0.027，其他所有P值&lt； 0.001）。45-54岁年龄组FIT的敏感性和特异性也略高，但差异较小，未达到统计学意义。在这个年龄组中，FIT和基于血液的检测都表现出相当低的敏感性（13.5%对10.6%），但高特异性（94.3%对93.8%）。 尽管间接比较的局限性（不同的研究人群，不同的招募年份，不同的患病率），我们旨在通过密切匹配纳入和排除标准和结果定义来减少这些局限性，但我们对两个大型筛查结肠镜检查队列的比较分析表明，在PREEMPT CRC研究中验证的研究性血液检测在检测APCL方面的敏感性和特异性都不如FIT。全球使用最广泛的非侵入性CRC筛查试验。两种检测方法检测结直肠癌的灵敏度相似。这些结果与我们之前通过比较ECLIPSE研究中美国食品和药物管理局批准的无细胞DNA （cfDNA）血液检测与FIT的诊断性能所证明的类似模式一致[3,7]。在最年轻的年龄组（45-54岁）中，基于血液的检查和FIT的诊断性能似乎是相当的，这表明基于血液的检查可能是该年龄组微创CRC筛查的合理替代FIT。然而，在这个年龄组中，研究参与者和晚期肿瘤的数量相当有限，特别是在BLITZ研究中，这导致敏感性估计的置信区间相对较宽。在美国最近的另一项研究中，在40-54岁的参与者中，FIT检测任何晚期肿瘤的敏感性（35/ 144,24.3%）和下一代多靶点粪便DNA检测（49/ 144,34.0%）b[8]都要高得多，这表明基于血液的检测（PREEMPT CRC研究中45-54岁年龄组的敏感性：10.6% [95% CI, 8.9%-12.6%]）在更年轻的筛查年龄也不会与这些粪便检测竞争。另一个有趣的观察结果，与ECLIPSE研究[3]中cfDNA血液检测的结果相同，应该在进一步的研究中进行跟进，即PREEMPT CRC研究中基于血液DNA甲基化检测的特异性随着年龄的增加而下降。PREEMPT CRC研究的作者假设，这种下降可能归因于DNA甲基化特征的年龄特异性改变。在进一步的研究中应该跟进的另一种假设可能是，它可能是由于在不同部位存在未被发现的癌症，在这种情况下，基于血液的测试可能比CRC筛查更有价值，阳性测试结果可能需要结肠镜检查以外的后续检查。总之，我们的分析证实，PREEMPT CRC研究中评估的血液检测对CRC的敏感性可能与FIT相当，但对APCL则不然，而且特异性更差。因此，与先前评估的无细胞DNA血液检测[3]一样，这种基于血液的检测不应被视为与基于fit的筛查同等替代或替代。对于那些厌恶粪便检测的人来说，血液检测可能仍然是有用的补充，否则他们可能会阻止他们进行CRC筛查。进一步的研究应着眼于提高血液检测APCL的敏感性。研究设计：Hermann Brenner， Teresa Seum。统计分析：Teresa Seum。手稿写作：Hermann Brenner。对手稿重要知识内容的关键性修改：所有作者。所有作者都阅读并批准了最终的手稿。作者声明无利益冲突。本研究部分由德国研究委员会（DFG）资助，资助号：BR1704/16-1)，联邦教育和研究部（BMBF，资助号01KD2104A）和德国癌症援助（DKH，资助号70114735和70115864）。资金来源在与研究有关的任何方面都没有作用。BLITZ研究得到了海德堡大学海德堡医学院伦理委员会（178/2005）和负责的国家医学协会的批准。该研究已在德国临床试验注册（DRKS-ID: DRKS00008737）注册。每位参与者都获得了书面知情同意书。支持本研究结果的数据可以在知情同意和保密规定的限制下，在合理的要求下提供。
{"title":"Diagnostic performance of a circulating tumor DNA-based blood test compared to fecal immunochemical test in colorectal cancer screening","authors":"Hermann Brenner,&nbsp;Teresa Seum,&nbsp;Megha Bhardwaj,&nbsp;Michael Hoffmeister","doi":"10.1002/cac2.70066","DOIUrl":"10.1002/cac2.70066","url":null,"abstract":"<p>Screening for colorectal cancer (CRC) has the potential to strongly reduce incidence and mortality of this common cancer [<span>1, 2</span>]. While fecal tests have long been established as non-invasive CRC screening tests, an intensive search for blood-based tests, which have been claimed to be easier to integrate into routine medical practice, is underway [<span>3, 4</span>]. Most recently, clinical validation of a circulating tumor DNA-based blood test for the detection of patterns of CpG (cytosine followed by guanine) dinucleotide methylation has been reported from the PREEMPT CRC study, a large, United States (US) based screening study including 27,010 participants of screening colonoscopy [<span>4</span>]. The study was sponsored by the manufacturer and reported with limited details about the laboratory analyses. With a sensitivity of 79.2% (95% confidence interval [CI], 68.4%-86.9%) for CRC detection and a specificity of 91.5% (95% CI, 91.2%-91.9%) for advanced colorectal neoplasia, the test met the pre-specified acceptance criteria, but the sensitivity for detecting advanced precancerous lesions (APCL) was low (12.5%). We aimed to compare the reported diagnostic performance of this blood-based test with that of the fecal immunochemical test (FIT), the best established and globally most widely used non-invasive CRC test [<span>5</span>], in a large population of screening colonoscopy participants from Germany.</p><p>Our analyses are based on data from the ongoing BLITZ study, whose design has been reported in detail elsewhere [<span>6</span>]. Briefly, participants undergoing screening colonoscopies were recruited in gastroenterology practices in Southern Germany and asked to complete a short questionnaire and provide a fecal sample prior to bowel preparation for the evaluation of non-invasive CRC screening tests. Participants for this analysis were selected from 10,061 participants recruited between 2008 and 2020 for whom the same quantitative FIT (FOB Gold, Sentinel Diagnostics, Milano, Italy) was performed. The diagnostic performance characteristics of the FOB Gold assay were determined at the manufacturer-recommended cutoff of 17.0 µg hemoglobin per gram of feces. To ensure comparability, we matched the inclusion and exclusion criteria as closely as possible to those of the PREEMPT CRC study, as outlined in the flow diagram in Supplementary Figure S1. We compared the sensitivity for detecting CRC (separately for any stage and stages I-III), advanced precancerous lesions (APCL) and any advanced neoplasia (CRC or APCL), and the specificity of the blood test reported from the PREEMPT CRC study to the corresponding metrics for the FIT in the BLITZ study. APCL included in situ or high-grade dysplasia, adenoma with villous growth pattern (≥ 25%), adenoma ≥ 1.0 cm, sessile serrated lesion ≥ 1.0 cm, and traditional serrated adenoma of any size. Differences were tested for statistical significance by two-sided chi-square tests at an alpha le","PeriodicalId":9495,"journal":{"name":"Cancer Communications","volume":"45 11","pages":"1496-1499"},"PeriodicalIF":24.9,"publicationDate":"2025-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://onlinelibrary.wiley.com/doi/epdf/10.1002/cac2.70066","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145198651","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
首页 上一页 下一页 尾页
类型
全部 化学•材料 生命科学 医学 物理 工程技术 环境•农林 材料科学 地球科学 法学 管理学 化学 环境科学与生态学 计算机科学 教育学 经济学 农林科学 人文科学 生物学 数学 物理与天体物理 心理学 综合性期刊 其他 工业工程 理学 历史学 农学 文学 信息工程
数据库
全部 ACS Publications Elsevier ieeexplore Springer The Royal Society of Chemistry Wiley
期刊
Cancer Communications
全部 Acc. Chem. Res. ACS Applied Bio Materials ACS Appl. Electron. Mater. ACS Appl. Energy Mater. ACS Appl. Mater. Interfaces ACS Appl. Nano Mater. ACS Appl. Polym. Mater. ACS BIOMATER-SCI ENG ACS Catal. ACS Cent. Sci. ACS Chem. Biol. ACS Chemical Health & Safety ACS Chem. Neurosci. ACS Comb. Sci. ACS Earth Space Chem. ACS Energy Lett. ACS Infect. Dis. ACS Macro Lett. ACS Mater. Lett. ACS Med. Chem. Lett. ACS Nano ACS Omega ACS Photonics ACS Sens. ACS Sustainable Chem. Eng. ACS Synth. Biol. Anal. Chem. BIOCHEMISTRY-US Bioconjugate Chem. BIOMACROMOLECULES Chem. Res. Toxicol. Chem. Rev. Chem. Mater. CRYST GROWTH DES ENERG FUEL Environ. Sci. Technol. Environ. Sci. Technol. Lett. Eur. J. Inorg. Chem. IND ENG CHEM RES Inorg. Chem. J. Agric. Food. Chem. J. Chem. Eng. Data J. Chem. Educ. J. Chem. Inf. Model. J. Chem. Theory Comput. J. Med. Chem. J. Nat. Prod. J PROTEOME RES J. Am. Chem. Soc. LANGMUIR MACROMOLECULES Mol. Pharmaceutics Nano Lett. Org. Lett. ORG PROCESS RES DEV ORGANOMETALLICS J. Org. Chem. J. Phys. Chem. J. Phys. Chem. A J. Phys. Chem. B J. Phys. Chem. C J. Phys. Chem. Lett. Analyst Anal. Methods Biomater. Sci. Catal. Sci. Technol. Chem. Commun. Chem. Soc. Rev. CHEM EDUC RES PRACT CRYSTENGCOMM Dalton Trans. Energy Environ. Sci. ENVIRON SCI-NANO ENVIRON SCI-PROC IMP ENVIRON SCI-WAT RES Faraday Discuss. Food Funct. Green Chem. Inorg. Chem. Front. Integr. Biol. J. Anal. At. Spectrom. J. Mater. Chem. A J. Mater. Chem. B J. Mater. Chem. C Lab Chip Mater. Chem. Front. Mater. Horiz. MEDCHEMCOMM Metallomics Mol. Biosyst. Mol. Syst. Des. Eng. Nanoscale Nanoscale Horiz. Nat. Prod. Rep. New J. Chem. Org. Biomol. Chem. Org. Chem. Front. PHOTOCH PHOTOBIO SCI PCCP Polym. Chem.
﹀
×
引用
GB/T 7714-2015
复制
MLA
复制
APA
复制
导出至
BibTeX EndNote RefMan NoteFirst NoteExpress
×
0
微信
客服QQ
Book学术公众号 扫码关注我们
反馈
×
意见反馈
请填写您的意见或建议
请填写您的手机或邮箱
×
提示
您的信息不完整，为了账户安全，请先补充。
现在去补充
×
提示
您因"违规操作"
具体请查看互助需知
我知道了
×
提示
现在去查看 取消
×
提示
确定
Book学术官方微信
Book学术文献互助
Book学术文献互助群
群 号：604180095
Book学术
文献互助 智能选刊 最新文献 互助须知 联系我们：info@booksci.cn
Book学术提供免费学术资源搜索服务，方便国内外学者检索中英文文献。致力于提供最便捷和优质的服务体验。
Copyright © 2023 Book学术 All rights reserved.
ghs 京公网安备 11010802042870号 京ICP备2023020795号-1