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更新于：2025-05-07

ATR-X Syndrome

ATR-X综合征

更新于：2025-05-07

基本信息

别名

ALPHA-THALASSEMIA/IMPAIRED INTELLECTUAL DEVELOPMENT SYNDROME, X-LINKED、ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, NONDELETION TYPE、ALPHA-THALASSEMIA/MENTAL RETARDATION SYNDROME, X-LINKED

+ [34]

简介

A rare, X-linked recessive inherited syndrome caused by mutations in the ATRX gene. It is characterized by intellectual disability, developmental delays, hypotonia, widely spaced eyes, small nose, low-set ears, tented upper lip, skeletal abnormalities, and a mild form of alpha thalassemia.

关联

项与 ATR-X综合征相关的药物

Cutamesine Hydrochloride

靶点

σ1 receptor

作用机制

σ1 receptor激动剂

在研机构

M's Science Corp. [+2]

原研机构

Santen SAS

在研适应症

肌萎缩侧索硬化 [+3]

非在研适应症

急性缺血性卒中 [+3]

最高研发阶段临床1期

首次获批国家/地区-

首次获批日期1800-01-20

项与 ATR-X综合征相关的临床试验

JPRN-jRCT2051220062

/ Not yet recruiting临床2期IIT

Exploratory study to investigate the safety and efficacy of NPJ005 in patients with ATR-X syndrome. - IACT21003

开始日期2022-07-14

申办/合作机构-

NCT03377556

/ Completed临床2期IIT

A Phase II Study of Talazoparib (BMN 673) in Patients With Homologous Recombination Repair Deficiency Positive Stage IV Squamous Cell Lung Cancer (Lung-Map Sub-Study)

This phase II trial studies how well talazoparib works in treating patients with homologous recombination repair deficiency (HRRD) positive stage IV squamous cell lung cancer that has come back after previous treatment. Talazoparib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

开始日期2017-03-03

申办/合作机构

National Cancer Institute

NCT04957069

/ CompletedN/AIIT

Comparison of Surgical Outcomes Between Avulsion Fracture of the Achilles Tendon and Conventional Achilles Tendon Rupture--a Retrospective Study

To compare the surgical outcomes between avulsion fracture of the Achilles tendon and conventional Achilles tendon rupture, collected and analysed information of patients preoperatively and postoperatively.

开始日期2013-01-01

申办/合作机构

北京大学第三医院（北京大学第三临床医学院）

100 项与 ATR-X综合征相关的临床结果

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100 项与 ATR-X综合征相关的转化医学

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0 项与 ATR-X综合征相关的专利（医药）

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269

项与 ATR-X综合征相关的文献（医药）

2025-03-01·Clinical Imaging

MRI-derived radiomics and end-to-end deep learning models for predicting glioma ATRX status: a systematic review and meta-analysis of diagnostic test accuracy studies

Review

作者: Bathla, Girish ; Ahmadzadeh, Amir Mahmoud ; Sotoudeh, Houman ; Ashoobi, Mohammad Amin ; Lomer, Nima Broomand

We aimed to systematically review and meta-analyze the predictive value of magnetic resonance imaging (MRI)-derived radiomics/end-to-end deep learning (DL) models in predicting glioma alpha thalassemia/mental retardation syndrome X-linked (ATRX) status. We conducted a comprehensive search across four major databases-Web of Science, PubMed, Scopus, and Embase. All the studies that assessed the performance of radiomics and/or end-to-end DL models for predicting glioma ATRX status were included. Quality assessment was performed using the Quality Assessment of Diagnostic Accuracy Studies-2 (QUADAS-2) criteria and the METhodological RadiomICs Score (METRICS). Pooled estimates for performance metrics were calculated. I-squared was used to assess heterogeneity, while subgroup and sensitivity analyses were performed to find its potential sources. Publication bias was assessed using Deeks' funnel plots. Seventeen and eleven studies were included in the systematic review and meta-analysis, respectively. Most of the studies had a low risk of bias and low concern for applicability according to the QUADAS-2. Also, most of them had good quality according to the METRICS. Meta-analysis showed a pooled sensitivity of 0.80 (95%CI: 0.71-0.96), a specificity of 0.82 (95%CI: 0.67-0.93), a positive diagnostic likelihood ratio (DLR) of 6.77 (95%CI: 4.67-9.82), a negative DLR of 0.15 (95%CI: 0.06-0.38), a diagnostic odds ratio of 30.36 (95%CI: 15.87-58.05), and an area under the curve (AUC) of 0.92 (95%CI: 0.89-0.94). Subgroup analysis revealed significant intergroup differences based on several factors. Radiomics models can accurately predict ATRX status in gliomas, enhancing non-invasive tumor characterization and guiding treatment strategies.

2025-02-08·Nucleic Acids Research

Elevated reactive oxygen species can drive the alternative lengthening of telomeres pathway in ATRX-null cancers

Article

作者: Goncalves, Tomas ; Kent, Thomas ; Cunniffe, Siobhan ; Clynes, David ; Rose, Andrew W ; Geiller, Helene E B ; Gibbons, Richard J ; Mattis, Natalie ; Mole, David R ; Humphrey, Timothy C ; van Bijsterveldt, Linda ; Rose, Anna M ; Ma, Tiffany S ; Hammond, Ester M

AbstractThe alternative lengthening of telomeres (ALT) pathway is a telomerase-independent mechanism for immortalization in cancer cells and is commonly activated in low-grade and high-grade glioma, as well as osteosarcoma. The ALT pathway can be activated under various conditions and has often been shown to include mutational loss of ATRX. However, this is insufficient in isolation and so other cellular event must also be implicated. It has been shown that excessive accumulation of DNA:RNA hybrid structures (R-loops) and/or formation of DNA–protein crosslinks (DPCs) can be other important driving factors. The underlying cellular events leading to R-loop and DPC formation in ALT cancer cells to date remain unclear. Here, we demonstrate that excessive cellular reactive oxygen species (ROS) is an important causative factor in the evolution of ALT-telomere maintenance in ATRX-deficient glioma. We identified three sources of elevated ROS in ALT-positive gliomas: co-mutation of SETD2, downregulation of DRG2, and hypoxic tumour microenvironment. We demonstrate that elevated ROS leads to accumulation of R-loops and, crucially, resolution of R-loops by the enzyme RNase H1 prevents ALT pathway activity in cells exposed to elevated ROS. Further, we found a possible causal link between the formation of R-loops and the accumulation of DPCs, in particular, formation of TOP1 complexes covalently linked to DNA (Top1cc). We also demonstrate that elevation of ROS can trigger over-activity of the ALT pathway in osteosarcoma and glioma cell lines, resulting in excessive DNA damage and cell death. This work presents important mechanistic insights into the endogenous origin of excessive R-loops and DPCs in ALT-positive cancers, as well as highlighting potential novel therapeutic approaches in these difficult-to-treat cancer types.

2025-01-06·Clinical Cancer Research

A Translational Study of the ATR Inhibitor Berzosertib as Monotherapy in Four Molecularly Defined Cohorts of Advanced Solid Tumors

Article

作者: Bullock, Andrea ; Zou, Lee ; Gao, Xin ; Kochupurakkal, Bose S. ; Cleary, James M. ; Muzikansky, Alona ; Cote, Gregory M. ; Shapiro, Geoffrey I. ; Do, Khanh ; Weekes, Colin D. ; McLoughlin, Daniel E. ; Park, Jong Chul ; Cheng, Michael L. ; Parikh, Aparna ; Yeku, Oladapo

AbstractPurpose:Preclinical studies have identified molecular correlates of sensitivity to ATR inhibition. This translational study was designed to test the ATR inhibitor berzosertib in patients with advanced solid tumors carrying alterations in ATRX, ataxia-telangiectasia–mutated (ATM), genes conferring replication stress (RS), or SDH.Patients and Methods:Patients were recruited to four cohorts: T1: ATRX-mutant leiomyosarcoma; T2: ATM-mutant solid tumors; T3: solid tumors with mutations in RS-associated genes; and T4: SDH-deficient gastrointestinal stromal tumors (GIST). Patients were treated with berzosertib 240 mg/m2 intravenously twice per week. Pretreatment and on-treatment biopsies were obtained in cohorts T1 to T3.Results:Patients with SDH-mutant GIST had the longest median progression-free survival (PFS; 229 days) with stable disease as the best response. Patients in the other cohorts experienced progressive disease within 4 months. There was no significant difference in PFS comparing outcomes in patients with/without mutations in ATM or RS genes. Decreased pS345-CHK1 levels in on-treatment biopsies indicated target engagement by berzosertib and were accompanied by substantial increases in levels of DNA damage (γ-H2AX) and RS (pKAP1) markers in a subset of patients. However, these biomarker changes did not translate to clinical benefit. In contrast, in cohorts T1 to T3, increased expression of SLFN11 on treatment correlated with clinical benefit (HR = 0.045; 95% confidence interval, 0.005–0.400).Conclusions:Across cohorts, only patients with SDH-mutant GIST experienced prolonged disease control. Despite evidence of target engagement, patients enrolled to all other cohorts had short PFS, suggesting rapid adaptation to ATR inhibitor monotherapy. Among these patients, those with tumors expressing SLFN11 during berzosertib exposure derived the most clinical benefit.

项与 ATR-X综合征相关的新闻（医药）

2025-04-12

·学术经纬

JCO | RAS和ALK突变在高危神经母细胞瘤中带来不利预后

撰文 | 李雯婕责编 | 周叶斌神经母细胞瘤是一种源于发育中周围神经系统的恶性肿瘤，具有高度异质性的分子特征和临床治疗结局。尽管采用了多模式综合治疗，高危神经母细胞瘤患者的生存率仍仅约50%，治疗现状不容乐观。部分高危患者中具有特定的分子特征，如节段性染色体畸变、MYCN扩增以及14%的患者存在ALK改变（突变/扩增）。复发的神经母细胞瘤中ALK和RAS-MAPK通路突变频率也显著升高。以往研究对于亚克隆突变在诊断时的临床意义尚未明确，不同回顾性研究由于采用的方法不同、对低频变异的检测灵敏度各异，导致相关报道存在矛盾。此外，克隆性与亚克隆性RAS 通路、TP53突变以及ATRX异常的预后意义也尚未见报道。近日，Yael P. Mossé等人在 Journal of Clinical Oncology 上发表题为 Frequency and Clinical Significance of Clonal and Subclonal Driver Mutations in High-Risk Neuroblastoma at Diagnosis: A Children's Oncology Group Study 的论文，采用统一、高灵敏度和特异性的超深度测序方法，对已完成的COG III期ANBL0532试验中的关键神经母细胞瘤相关基因进行检测，明确这些基因异常的发生率及其对患者预后的影响，定义具有预后意义的变异等位基因频率（VAF）阈值，为临床治疗决策提供更可靠的依据。首先，作者统计分析了242例高危神经母细胞瘤患者的基线特征。从分期来看，ALK异常患者中III期和IV期占比远高于ALK野生型患者，提示ALK状态可能与疾病进展相关。MYCN扩增在ALK异常患者中更常见，且二者共同发生对预后影响大。其次，作者运用定制的NGS panel，检测发现38%的患者肿瘤存在致病改变。其中，ALK异常的比例为24.8%，包括21.5%的激活突变和3.3%的异常扩增。RAS通路突变占7.9%，TP53致病性变异占4.5%，ATRX功能缺失性异常占9%。上述数据表明，多种基因的异常在高危神经母细胞瘤中较为常见，为后续研究这些异常与患者预后的关系提供了重要依据，也提示针对这些基因异常开发靶向治疗方案的潜在方向。再次，作者聚焦于ALK和RAS-MAPK通路变异（VAF≥5%）对高危神经母细胞瘤患者预后的影响。研究表明，携带任何ALK异常的患者预后较差，5年无事件生存率（EFS）和总生存率（OS）低于ALK野生型患者。其中，ALK扩增患者预后尤其不佳。携带VAF≥5%激活型ALK突变的患者，其EFS和OS也明显低于野生型。对于RAS通路，虽然整体突变组与野生型组无差异，但VAF≥5%的激活突变患者预后更差。这表明ALK和RAS-MAPK通路特定变异与不良预后相关，为临床风险评估和治疗决策提供了关键依据。图1：携带ALK突变患者的VAF分层预后图：携带RAS突变患者的VAF分层预后MYCN扩增与ALK异常在高危神经母细胞瘤中经常同时出现，且这种共现预示着较差的预后。同时存在MYCN扩增和ALK突变（VAF≥5%）的患者，5年EFS和OS明显低于MYCN扩增但ALK野生型的患者。不过，ALK突变（VAF≥5%）在无 MYCN 扩增的肿瘤中对预后的影响，因患者数量少难以定论。这表明 MYCN 扩增与 ALK 异常的共现是影响患者预后的重要因素，对评估病情和制定治疗策略有重要意义。图：MYCN扩增和ALK突变并存患者的EFS和OS由于TP53突变患者数量较少，对其预后影响的评估受限。而ATRX异常似乎对预后影响不明显，携带ATRX异常的患者与ATRX野生型患者相比，5年EFS和OS差异均无统计学意义。但总体样本量有限，这些结论仍需进一步研究验证。综上所述，本研究确定了高危神经母细胞瘤诊断时潜在可治疗的基因异常发生率，发现ALK改变的总体发生率高于以往报道，且不同ALK突变对患者预后影响不同。同时，该研究表明MYCN扩增与ALK突变共现频率较高，这类患者预后差，研究支持将VAF≥5%作为ALK异常患者接受ALK靶向药物劳拉替尼治疗的标准。此外，该研究强调了对高危神经母细胞瘤患者进行早期分子分层的重要性，为识别超高危患者和开发创新疗法提供依据。撰文责编制作排版 | 车洁校对 | uu延伸阅读针对难治恶性脑瘤的潜在 “first-in-class” 抗癌小分子有望在今年完成新药审评！*本文由深圳市拾玉儿童公益基金会“儿童肿瘤前沿”团队编译或约稿，文中图表均源引自文献原文。本文著作权归文章作者所有，欢迎个人转发分享，未经允许禁止转载，作者拥有所有法定权利，违者必究。如需转载，请留言或联系shiyu@curekids.cn。本文旨在分享儿童肿瘤科研前沿成果，不是治疗方案推荐。如需获得疾病治疗方案指导，请前往正规医院就诊。▼滑动查看更多▼原文摘要（Abstract）Purpose: Relapsed high-risk neuroblastomas (NBLs) are enriched for targetable mutations in ALK and RAS-MAPK pathways, yet the prognostic effect of these aberrations and relevance of subclonal mutations at diagnosis remain undefined. We describe the spectrum and clinical significance of clonal and subclonal pathogenic alterations in high-risk NBL.Methods: We developed a focused high-risk NBL sequencing panel including ALK, NRAS, KRAS, HRAS, BRAF, PTPN11, TP53, and ATRX genes for ultra-deep sequencing and applied this assay to 242 pretherapy tumors from patients enrolled on the phase III trial Children's Oncology Group ANBL0532. We assessed the effect of clonal and subclonal mutations on event-free survival (EFS) and overall survival (OS).Results: ALK-activating mutations occurred in 21.5% of tumors (n = 52, 30 clonal, 22 subclonal), and 3.3% (n = 8) showedALKamplification. EFS and OS for patients with anyALK-aberrant tumor were inferior to patients with wild-type (WT)ALKtumors (5-year OS 37.7%v66.3%; hazard ratio [HR], 1.992;P= .0007). EFS and OS for patients with tumors harboring activatingALKmutations ≥5% variant allele frequency (VAF) were inferior toALKWT (5-year OS 37.7%v66.3%; HR, 1.966;P= .0041). The 5-year EFS and OS for patients withALK-amplified tumors were 25.0%. RAS pathway mutations occurred in 7.9% of tumors (n = 19; four clonal, 15 subclonal), with EFS and OS for those with VAF ≥5% inferior to RAS-WT patients (5-year OS 19.1%v60.0%; HR, 3.021;P = .0168).Conclusion: Ultra-deep sequencing of high-risk NBLs demonstrates that oncogenic aberrations are more prevalent at diagnosis than previously recognized. ALK and RAS pathway aberrations confer inferior outcomes in patients treated with contemporary therapy, emphasizing the need for novel therapeutic approaches.DOI: 10.1200/JCO-24-02407👇点击此处，直达原文

临床3期临床结果申请上市AACR会议临床终止

2024-05-14

·医药观澜

下一个“合成致死”新星？阿斯利康、罗氏、恒瑞、英派等都看中的抗癌新靶点是它！

▎药明康德内容团队报道“合成致死”是指两个非致死基因同时被抑制，导致细胞死亡的现象。利用这一机制找到肿瘤中的特异突变，再找到它的“合成致死搭档”，将有望特异性杀死癌细胞。众所周知的PARP抑制剂是首个利用“合成致死”概念在临床上取得成功的药物。PARP抑制剂之外，科学家们也在探索一些其它的“合成致死”新靶点，以期给癌症患者带来更多的治疗选择，ATR就是被寄予厚望的靶点之一。据不完全统计，当前全球范围内已有至少15款ATR抑制剂进入到临床试验阶段，研发公司既有诸如阿斯利康、德国默克、罗氏、拜耳等国际大药企，也有恒瑞医药、英派药业、正大天晴等中国公司。那么，ATR与疾病到底有何关联？当前，ATR抑制剂的开发现状是怎么样的？它们又有望惠及哪些患者？本文中就让我们来一起了解下。图片来源：123RF——✦ATR：癌症治疗新靶点✦——2005年，距离首次报道癌细胞有丝分裂图异常一个多世纪后，两项开创性的研究揭示了人类癌症中DNA损伤反应（DDR）的广泛激活。这些研究表明，癌细胞中基因组不稳定性的起源可能与DNA复制过程中出现的问题有关。此后不久，几份报告证实癌基因的表达会诱导复制应激（Replication Stress，RS）[2]。ATR中文全称是共济失调毛细血管扩张症和Rad3相关蛋白丝氨酸/苏氨酸激酶，它与毛细血管扩张共济失调突变（ATM）、DNA依赖性蛋白激酶催化亚基(DNA-PKcs)一起形成DNA损伤反应的核心激酶。虽然这三种激酶的序列相似，但它们针对的DNA损伤反应并不相同。其中，ATM和DNA-PKcs主要出现在DNA双链断裂修复中，ATR主要出现在复制应激中。图片来源：123RF现在人们已经知道，ATR是PI3K相关激酶（PIKK）家族的成员，也是细胞复制应激反应（RS Response，RSR）的中心介质，其调节细胞周期检查点的激活和DNA复制，以控制细胞分裂并保护基因组完整性。ATR主要感知复制叉停滞位点或其他DNA损伤来源引起的广泛单链DNA断裂并被激活。激活后，ATR通过启动一系列协调的下游反应来转导该信号，最终导致细胞周期进程的停滞和停滞的复制叉的稳定，从而实现DNA修复。研究发现，激活后的ATR会磷酸化多种下游底物，尤其是丝氨酸/苏氨酸蛋白激酶CHK1。抑制ATR-CHK1信号通路会导致广泛的基因组不稳定、DNA双链断裂和复制叉崩溃。此外，抑制ATR还会导致不适当的细胞周期进展，无论复制压力或DNA损伤如何，都会过早进入有丝分裂，从而引发有丝分裂灾难和细胞凋亡[1]。总体而言，现有数据支持RS是癌症基因组不稳定性的主要来源，并且不断受到RSR的抑制。RSR因子在具有高水平复制损伤的癌症中被积极选择，这使得肿瘤细胞能够在RS存在的情况下生长。而且，越来越多的证据表明，许多具有高水平RS的肿瘤特别容易受到ATR缺失的影响。这些研究发现为开发ATR抑制剂治疗癌症提供了基础。——✦ATR的“合成致死”搭档✦——生物标志物的测定对于ATR抑制剂的开发至关重要，然而目前尚未建立起针对ATR抑制剂反应的整体生物标志物。目前正在研究的潜在生物标志物包括容易导致复制应激累积的个体基因组改变、能表明RSR升高的基因特征等等。ATM在DDR和RS的调节中与ATR具有重叠的功能，因此ATM功能障碍被描述为通过增加对ATR-CHK1信号通路的依赖，从而与ATR抑制剂组成“合成致死”搭档。因为染色质重塑复合物也部分参与DNA修复，具有肿瘤抑制功能的特定表观遗传修饰因子的缺陷也被认是ATR抑制作用的“合成致死”搭档，例如ARID1A、SETD2、PBRM1和转录激活因子BRG1（也称为SMARCA4）等。▲在合成致死相互作用的筛选中已鉴定出具有作为生物标志物潜在价值的基因组改变。（图片来源：参考资料[1]）众所周知，癌细胞利用端粒酶或替代性端粒延长(ALT)来维持端粒长度并实现复制永生。在癌细胞中，ATRX的缺失会导致细胞周期调节受损以及DNA复制后RPA-端粒关联持续存在。有研究发现，在ATRX缺失的癌细胞中抑制ATR会导致ALT破坏并引发染色体断裂和细胞凋亡，预示ATRX异常也可能是ATR抑制剂的潜在生物标志物。除了上述单个基因组改变之外，化学遗传学筛选还可以鉴定广泛的其他潜在基因组改变，作为ATR抑制剂的“合成致死”搭档，其中包括：RNAse H2复合体缺陷；APOBEC3A/B的改变；致癌基因激活，例如MYC扩增；RAS突变或NF1功能丧失；其他细胞周期检查点/DNA修复蛋白的缺陷，包括CCNE1扩增、TOPBP1、CDK12和ERCC1/XRCC1；剪接体热点突变，包括SF3B1、U2AF1和SRSF2；其他的还包括SPOP突变、PAX3-FOXO1融合癌基因表达、STAG2丢失或胞质铁硫(Fe-S)蛋白组装复合物的破坏等。不过，文章也指出，仍需要更进一步的数据来更好地理解这些改变与ATR抑制剂临床应用的相关性。——✦10余款ATR抑制剂进入临床阶段✦——ATR在调节RSR中的关键作用使该蛋白成为抗癌药物开发的一个有吸引力的靶标，可用于治疗复制应激升高或DNA修复缺陷的癌症。然而，由于ATR蛋白体积较大，开发特异性且有效的ATR抑制剂具有挑战性。同时，因为ATR活性仅限于S-G2期，并且所有磷脂酰肌醇3激酶相关激酶（PIKK）中的活性位点具有高度同源性，这使药物的选择性变得复杂。第一种被发现能抑制ATR的化学物质是咖啡因。然而，咖啡因在实验中使用的剂量非常高，它也会抑制其它几种PIKK。接下来，天然存在的化合物五味子素B被证明可以抑制ATR并消除G2-M期的检查点激活，尽管使用的浓度也很高。后来，科学家们通过几种不同的方法发现了有效的ATR抑制剂。例如，研究人员通过添加4-羟基-他莫昔芬可以在哺乳动物细胞中随意释放ATR活性的细胞系统的开发，使得基于细胞的高通量显微镜筛选特异性阻断ATR活性的化合物成为可能。同时，还有研究人员使用CHK1磷酸化作为ATR激活的指标发现CDK2抑制剂NU6027也可以作用于ATR。此外，科学家们直接使用重组ATR进行体外激酶反应，也鉴定了一系列以ATR为靶点而不影响ATM或DNA-PKcs的化合物。随着ATR领域研究的不断进展，全球范围内已涌现出了越来越多的ATR抑制剂。据不完全统计，目前至少有15款ATR抑制剂已进入到临床试验阶段，研发企业既有阿斯利康（AstraZeneca）、德国默克（Merck KGaA）、罗氏（Roche）、拜耳（Bayer）等国际药企，也有英派药业、正大天晴、恒瑞医药、泰德制药、智康弘义等中国公司。从适应症来看，这些在研ATR抑制剂主要针对不同的实体瘤，只有少数在研药物在开发针对血液癌症的临床研究。研究发现，单药之外，ATR抑制剂与化疗、PARP抑制剂、PD-1/-L1抑制剂等联用也能表现出良好的治疗效果。因此，联合治疗已成为ATR抑制剂的一个主要探索方向。从上表可以看出，目前有不少在研ATR抑制剂正在开展组合用药的临床研究，用药“搭档”主要包括放射治疗、化疗、PD-1/PD-L1抑制剂、PARP抑制剂。▲ATR抑制剂的潜在联合用药搭档（图片来源：参考资料[1]）上述靶点之外，在过去几年中，临床前研究也发现了越来越多其它在被抑制后有望与ATR抑制剂产生协同作用的潜在靶点，包括AXL、BET、exportin-1、Aurora激酶、CTP合酶和雄激素信号传导等。此外，还有研究发现ATR抑制剂和抗体偶联药物（ADC）组合也有可能产生协同的抗肿瘤作用。 ——✦挑战和未来✦——整体而言，ATR抑制剂的开发还处于早期阶段，目前尚未有产品上市。根据今年2月发表在Nature Reviews Clinical Oncology上的一篇综述，围绕ATR抑制剂未来开发的几个挑战仍然存在，包括：1）如何确定生物标志物，以便可以精准地选择患者；2）如何建立最佳给药方案和合理的组合治疗策略，使ATR抑制剂的获益最大化，同时使毒性最小化；3）如何分析该药物类别内药物之间的特异性差异性。这篇文章指出，ATR领域的进一步药物开发工作应优先考虑预测生物标志物的识别和完善，阐明ATR抑制剂的耐药机制，以及开发合理的组合，同时了解ATR功能的亚效性及其与不同RSR机制的串扰。希望随着研究的进展，靶向ATR的药物开发领域能取得更多突破，早日为癌症患者带来新的治疗选择。参考资料：（可上下滑动查看） [1]Ngoi, N.Y.L., Pilié, P.G., McGrail, D.J. et al. (2024) Targeting ATR in patients with cancer. Nat Rev Clin Oncol . https://doi.org/10.1038/s41571-024-00863-5[2]Lecona, E., Fernandez-Capetillo, O. (2018)Targeting ATR in cancer. Nat Rev Cancer . https://doi.org/10.1038/s41568-018-0034-3[3]中国药物临床试验登记与信息公示平台官网. From http://www.chinadrugtrials.org.cn/index.html[4]Clinicaltrials网站，From https://www.clinicaltrials.gov/[5]各公司公开资料。本文来自药明康德内容团队，欢迎个人转发至朋友圈，谢绝媒体或机构未经授权以任何形式转载至其他平台。转载授权请在「医药观澜」微信公众号留言联系我们。其他合作需求，请联系wuxi_media@wuxiapptec.com。免责声明：药明康德内容团队专注介绍全球生物医药健康研究进展。本文仅作信息交流之目的，文中观点不代表药明康德立场，亦不代表药明康德支持或反对文中观点。本文也不是治疗方案推荐。如需获得治疗方案指导，请前往正规医院就诊。