更新于：2024-11-01

AR

更新于：2024-11-01

基本信息

别名

AIS、Androgen receptor、AR

+ [11]

简介

Steroid hormone receptors are ligand-activated transcription factors that regulate eukaryotic gene expression and affect cellular proliferation and differentiation in target tissues (PubMed:19022849). Transcription factor activity is modulated by bound coactivator and corepressor proteins like ZBTB7A that recruits NCOR1 and NCOR2 to the androgen response elements/ARE on target genes, negatively regulating androgen receptor signaling and androgen-induced cell proliferation (PubMed:20812024). Transcription activation is also down-regulated by NR0B2. Activated, but not phosphorylated, by HIPK3 and ZIPK/DAPK3. Lacks the C-terminal ligand-binding domain and may therefore constitutively activate the transcription of a specific set of genes independently of steroid hormones. Lacks the C-terminal ligand-binding domain and may therefore constitutively activate the transcription of a specific set of genes independently of steroid hormones.

关联

418

项与 AR 相关的药物

Berdazimer sodium

靶点

作用机制

AR拮抗剂 [+1]

在研机构

Lnhc, Inc. [+2]

原研机构

NVN Liquidation, Inc.

在研适应症

传染性软疣 [+1]

非在研适应症

尖锐湿疣 [+2]

最高研发阶段批准上市

首次获批国家/地区

美国

首次获批日期2024-01-05

Rezvilutamide

瑞维鲁胺

靶点

作用机制

AR拮抗剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

中国

首次获批日期2022-06-28

Proxalutamide

普克鲁胺

靶点

作用机制

AR拮抗剂

在研机构

原研机构

在研适应症

非在研适应症

最高研发阶段批准上市

首次获批国家/地区

巴拉圭

首次获批日期2021-07-16

2,288

项与 AR 相关的临床试验

NCT06660862 / Not yet recruiting临床4期IIT

DAROSTEP: Evaluating Step Counts as a Biomarker and Its Relationship on Treatment Outcomes in Vulnerable Patients With Metastatic Hormone-Sensitive Prostate Cancer on Darolutamide and Androgen Deprivation Therapy

This prospective clinical trial aims to investigate the impact of darolutamide in combination with standard-of-care androgen deprivation on physical activity, specifically step count, and its correlation with important markers of safety in vulnerable adults who screen positive by a brief geriatric assessment (GA) and metastatic hormone-sensitive prostate cancer.

开始日期2025-11-01

申办/合作机构

The University of Chicago

NCT06592924 / Not yet recruiting临床3期IIT

A Randomized Clinical Trial for the Addition of Docetaxel to Androgen Receptor Pathway Inhibitors in Patients With Metastatic Castration Sensitive Prostate Cancer Without Deep PSA Response

This study is being done to answer the following question: can the chance of prostate cancer growing or spreading be lowered by adding a drug to the usual combination of drugs?
This study would like to find out if this approach is better or worse than the usual approach for prostate cancer.
The usual approach for patients who are not in a study is hormone treatment with Androgen Deprivation Therapy (ADT) and Androgen-Receptor Pathway Inhibitor (ARPI).

开始日期2025-01-15

申办/合作机构

Canadian Cancer Trials Group

[+4]

100 项与 AR 相关的临床结果

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100 项与 AR 相关的转化医学

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0 项与 AR 相关的专利（医药）

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33,539

项与 AR 相关的文献（医药）

2025-03-01·Biomaterials

Mesoporous cerium oxide nanoenzyme for Efficacious impeding tumor and metastasis via Conferring resistance to anoikis

Article

作者: Zhang, Xiaolong ; Wang, Peiyuan ; Yao, Hanlin ; Lin, Ziguo ; Wang, Yunhao ; You, Xinyu ; Liu, Yang ; Ding, Lei ; Feng, Juan ; Sun, Wen

Tumor cells can survive when detached from the extracellular matrix or lose cell-to-cell connections, leading to a phenomenon known as anoikis resistance (AR). AR is closely associated with the metastasis and proliferation of tumor cells, enabling them to disseminate, migrate, and invade after detachment. Here, we have investigated a novel composite nanoenzyme comprising mesoporous silica/nano-cerium oxide (MSN-Ce@SP/PEG). This nanoenzyme exhibited satisfactory catalase (CAT) activity, efficiently converting high levels of H₂O₂ within tumor cells into O₂, effectively alleviating tumor hypoxia. Furthermore, MSN-Ce@SP/PEG nanoenzyme demonstrated high peroxidase (POD) activity, elevating reactive oxygen species (ROS) levels and attenuating AR in hepatocellular carcinoma (HCC) cells. The MSN-Ce@SP/PEG nanoenzyme exhibited satisfactory dual bioactivity in CAT and POD and was significantly enhanced under favorable photothermal conditions. Through the synergistic effects of these capabilities, the nanoenzyme disrupted the epithelial-mesenchymal transition (EMT) process in detached HCC cells, ultimately inhibiting the recurrence and metastasis potential of anoikis-resistant HCC cells. This study represents the first report of a novel nanoenzyme based on mesoporous silica/nano-cerium oxide for treating AR in HCC cells, thereby suppressing HCC recurrence and metastasis. The findings of this work offer a pioneering perspective for the development of innovative strategies to prevent the recurrence and metastasis of HCC.

2025-02-01·Combinatorial Chemistry & High Throughput Screening

Identification of Novel Hub Genes Associated with Inflammation and Autophagy in Astragaloside Membranaceus ameliorates Lupus Nephritis by Bioinformatics Analysis and Molecular Dynamics Simulation

Article

作者: Fang, Jingai ; Kong, Kaili ; Li, Rui ; Liu, Ting ; Qiao, Xiaomei ; Wang, Xiaoxia ; Zhang, Xiaodong

Background:Lupus nephritis is an autoimmune disease, and its pathogenesis involves inflammation and autophagy disorders. Studies have demonstrated that Astragalus membranaceus can effectively suppress the progression of LN, but the underlying therapeutic target is still unclear.Objection:This study aimed to investigate the therapeutic target whereby AM ameliorates LN.Method:We downloaded AM and LN-related chips from the TCMSP and GEO databases, respectively. We selected the two compound targets for the subsequent analysis via WGCNA, and constructed protein interaction networks of compound targets and determined the core targets. GO, KEGG analyses were conducted on compound targets to identify enriched functional and genomic pathways. The core genes were further validated in clinical and external datasets. Molecular docking of AS with the core targets was performed using the AutoDock software, and molecular dynamics simulation was conducted for the optimal core protein ligand obtained by molecular docking by Gromacs 2020.6 software.Result:We obtained 10 core targets, namely IL-1β, EGF, CCND1, CASP3, STAT1, PTGS2, PPARγ, AR, CXCL10, and KDR, from the 24 compound targets identified. The results of the GO enrichment analysis mainly included cell growth regulation. The results of the KEGG enrichment analysis showed that 7 out of 23 valid targets were significantly enriched in the mitogen-activated protein kinase pathway (p < 0.01). Combined with the clinical datasets, we found that IL-1β, EGF, CCND1, CASP3, STAT1, PTGS2, and PPARγ have high diagnostic values for LN. In the validation dataset, all the core targets were significantly differentially expressed, except for EGF deletion. The molecular docking and molecular dynamics simulation results showed that AM and IL- 1β, CASP3, STAT1, and PPARγ all had binding energies < -5 kJ·mol-1 and good binding properties.Conclusion:IL-1β, CASP3, STAT1, and PPARγ could be potential biomarkers and therapeutic targets in AM ameliorates LN.

2025-01-01·Journal of Affective Disorders

Bidirectional association between allergic rhinitis and attention-deficit/hyperactivity disorder: A systematic review and meta-analysis

Article

作者: Gui, Xiongbin ; Wei, Jingxuan ; Li, Yang ; Wu, Qiuye ; Lei, Bingbing

BACKGROUNDThis meta-epidemiological study seeks to further investigate the reciprocal relationship between allergic rhinitis (AR) and attention-deficit/hyperactivity disorder (ADHD).METHODSA comprehensive search of the databases was conducted up to March 3, 2024. We performed a synthesis and meta-analysis of odds ratios and their corresponding 95 % confidence intervals using Stata 14.0. Funnel plot analysis and Egger's regression test were utilized to assess potential publication bias.RESULTSEighteen articles involving 4,289,444 participants were included. AR patients had an increased risk of developing ADHD (OR: 1.83; 95 % CI: 1.37-2.43), while ADHD patients were also more likely to have AR (OR: 1.38; 95 % CI: 1.11-1.72). Subgroup analysis indicated a predisposition of AR patients to autism spectrum disorder (OR: 1.34; 95 % CI: 0.86-1.0) and a higher risk of ADHD in cohort studies (OR: 1.90; 95 % CI: 1.26-2.88). Female AR patients were more likely to develop ADHD than males (OR: 1.86; 95 % CI: 1.43-2.43), and children aged ≤8 years with AR were at greater risk for ADHD compared to older children (OR: 1.75; 95 % CI: 1.14-2.69).CONCLUSIONSThis meta-analysis confirms a bidirectional association between AR and ADHD, indicating that they are mutually independent risk factors.

1,481

项与 AR 相关的新闻（医药）

2024-10-30

·GBIHealth

辉瑞Y24Q3财报速读：收入177亿美元，肿瘤业务增长31%

2024年10月29日，辉瑞发布2024年第三季度财务业绩。第三季度（报告期），公司收入177.02亿美元，同比增长32%（按固定汇率计算，下同）。前三季度，公司收入458.64亿美元，同比增长3% 前三季度，公司收入458.64亿美元，同比增长3%。鉴于公司表现，全年收入指引提升15亿美元至610~640亿美元。按部门划分报告期内普通护理业务收入90.6亿美元，同比增长44%。普通护理业务中，公司新冠疗法Paxlovid收入27.03亿美元，比去年同期高出25亿美元，主要由于全球新一轮疫情催生更高的需求，尤其在美国。2024年第三季度公司向美国战略国家储备交付了100万疗程药品，收入4.42亿美元。新冠疫苗Comirnaty收入14亿美元，同比增长9%。除新冠产品外，公司其他产品的总收入为136亿美元，同比增长14%。专科护理业务收入42.89亿美元，同比增长15%。专科护理业务中，罕见病氯苯唑酸类药物（Vyndaqel, Vyndamax, Vynmac）收入最高，达14.47亿美元，同比增长63%，这主要得益于该药在美国和国际发达市场的需求较大。肿瘤业务收入40.43亿元，同比增长31%。肿瘤业务中，爱博新（哌柏西利）销售额居首，达10.87亿美元，同比下降12%；其次为雄激素受体抑制剂安可坦（恩扎卢胺），销售额5.61亿美元，同比增长28%； 2023年收购的Seagen旗下产品Padcev（维恩妥尤单抗）、靶向CD30的Adcetris（维布妥昔单抗）、靶向HER2的Tukysa（妥卡替尼）、靶向组织因子（TF）的Tivdak总共收入8.35亿美元。大部分辉瑞管线进展顺利，但基因疗法Fordadistrogene Movaparvovec治疗假肥大性肌营养不良的Ⅲ期临床研究未达主要终点。全球医疗情报领导者解锁隐藏在数据中的商业潜力关于 G B I ” 自从2002年成立以来，GBI始终以技术为驱动，为药企、器械及行业相关服务商提供贯穿生命周期的全球药品市场竞争数据、全球行业资讯、HCPs洞察、全国医疗器械数据等商业信息与洞察，助力企业在进行战略布局和决策时，脱颖而出。历经20余年的深耕细作GBI已成为95%以上跨国药企、国内头部药企、咨询与投资机构等医疗圈灯塔用户值得信赖的长期合作伙伴。联系我们投稿 | 发稿 | 媒体合作 ▶ zhangxinyue13@baidu.com 数据库 | 咨询服务 | 资讯追踪 ▶ 点击左下“阅读原文”完成表单填写点击阅读原文，解锁完整双语新闻

财报临床3期疫苗抗体药物偶联物并购

2024-10-29

·药渡

解决传统PROTACs、miRNA疗法关键挑战，miRiaTAC开启精准抗癌新征程

来源：药渡撰文：balabala 编辑：维他命近期，南京大学张晶晶教授研究团队针对上述新型PROTAC策略的局限性，以miRNA触发的DNA编码的pre-PROTAC的形态调节为依据，成功开发出一种全新的miRNA启动的组装pre-PROTAC平台——miRiaTAC。 PART. 01 传统PROTAC技术所面临的挑战靶向蛋白水解嵌合体（PROTACs）作为一种极具前景的治疗策略，通过利用细胞天然蛋白质降解机制靶向消除疾病相关蛋白，展现出与传统占位驱动抑制剂不同的独特优势，如在低剂量下发挥催化作用以及降解顽固蛋白等（图1）。图1. 基于靶蛋白降解的各种嵌合体策略然而，在临床应用中，PROTACs面临着诸多挑战。首先，肿瘤选择性差是一个突出问题。由于无法精准区分肿瘤细胞和正常细胞，PROTACs在发挥作用时可能会对正常组织造成不良影响，降低了治疗的特异性。这种缺乏肿瘤选择性的特性可能导致治疗效果受限，同时增加了患者出现副作用的风险。其次，蛋白质不受控制的降解带来了非癌组织全身毒性风险。PROTACs引发的蛋白质降解若失去控制，可能会对正常组织和器官的蛋白质平衡产生破坏，干扰人体正常的生理功能。这种全身毒性风险不仅影响患者的生活质量，还可能对治疗的安全性和可持续性构成威胁。此外，过度激活也是PROTACs面临的挑战之一。过度激活可能引发一系列未知的生理反应或副作用，进一步加重患者的病情或导致新的健康问题。这种不确定性增加了治疗的复杂性和风险。因此，研发一种按需开关策略，以实现选择性激活和终止PROTACs介导的蛋白质降解，成为当前迫切需要解决的问题。这将有助于提高PROTACs的治疗特异性和安全性，为其在临床治疗中的广泛应用奠定基础。 PART. 02 新型PROTAC技术对副作用的优化策略 1 Nano-PROTACs策略 2023年7月，国家纳米科学中心的王浩研究员开发了一种用于肿瘤治疗的Nano-PROTACs技术，该技术旨在解决传统PROTACs的问题。其设计的Nano-PROTAC 系统由含特定结构域的两个肽基前体组成，在肿瘤细胞高GSH水平下经点击反应自组装成有序纳米结构。图2. 原位自组装Nano-protacs的示意图体外研究表明，它能形成多元纳米复合物，有效降解EGFR和AR等蛋白，且具有剂量依赖性和抗钩效应。体内研究显示，Nano-PROTACs可在肿瘤部位富集和保留，在荷瘤小鼠模型中呈现剂量依赖性的肿瘤抑制效果，通过降解靶蛋白诱导凋亡发挥抗肿瘤作用，同时该系统具有良好生物相容性和细胞选择性。 Nano-PROTAC技术虽然在蛋白降解领域显示出巨大潜力，但仍面临靶点单一、不能即时终止降解过程和制造成本昂贵等多方面的挑战。 2 Ligation to Scavenging策略在探索靶蛋白可控降解以及按需终止相关问题的进程中，中国药科大学姜正羽教授研究团队于2023年3月开创性地提出了一种能够即时终止蛋白降解过程的连接-清除（Ligation to Scavenging）策略（图3）。图3. 受控的PROTACs和连接-清除系统示意图该策略由经反式环辛烯（TCO）修饰的树枝状大分子（PAMAM-G5-TCO）以及四嗪标记的PROTACs（Tz-PROTACs）这两个关键部分构成。其中，PAMAM-G5-TCO能够借助逆电子需求的Diels-Alder反应（IEDDA），快速且有效地清除细胞内处于游离状态的PROTACs，进而达成对靶向蛋白降解过程的终止调控。通过这一调控机制，那些已经出现下调情况的靶蛋白能够逐步恢复到正常水平。在研究过程中，研究人员针对BET蛋白、PARP蛋白等多个底物蛋白展开了降解终止的相关实验，充分论证了该策略具备可靠性以及广泛的适用性，为PROTAC降解技术装上了可靠的“刹车”。然而，该策略在选择性和特异性方面可能会受到特定靶蛋白以及降解条件的限制，这一局限给这一颇具潜力的策略未来发展蒙上了一层阴影。 3 DbTAC策略 2023年7月，中国药科大学马祎教授研究团队受到DNA框架所具备的可寻址性、可编程性以及刚性特质的启发，成功开发出基于共价DNA框架的PROTACs（DbTACs）。这种DbTACs能够借助简单的生物正交化学以及自组装方式，实现高通量合成（图4）。图4. 选择性靶向蛋白降解的DbTACs平台设计示意图在其构建过程中，采用DNA四面体作为模板，此模板能够精准地定义每个原子的空间位置。基于这一特性，通过在模板上对POI和E3连接酶的配体进行精确的定位操作，就能够对配体间距进行有效控制，其范围可从8 Å到57 Å。研究人员经研究发现，具有配体之间最佳连接长度的dbtac，展现出了更高的降解率以及更强的结合亲和力。此外，具有三价配体组装的双特异性DbTACs（双-DbTACs）表现出独特优势，它能够在确保对蛋白质亚型进行高度选择性降解的同时，实现对多个靶点的消耗。而且，当运用不同类型的弹头，如小分子、抗体以及DNA基元时，DbTACs在针对多种靶标进行降解方面彰显出强大的功效，这些靶标涵盖了位于不同细胞区室的蛋白激酶和转录因子等。 DbTACs这一策略突破了传统PROTAC分子仅能降解单一靶点的局限，然而，它也面临着一些挑战，例如无法即时终止降解过程且不具有细胞选择性等。 4 Dual-PROTAC策略 2021年5月，华中科技大学同济药学院李华教授研究团队，鉴于单一靶点治疗存在诸多局限，创新性地提出了双靶向PROTAC分子（Dual-PROTAC）这一概念。受到双靶向药物的启发，研究人员设计并合成了一种能够同时对表皮生长因子受体（EGFR）和聚（ADP-核糖）聚合酶（PARP）进行降解的双靶点PROTAC分子。在合成过程中，研究团队巧妙地运用天然氨基酸作为连接体，并选取吉非替尼、奥拉帕利以及CRBN或VHL的E3配体作为底物来合成相关分子（图5）。图5. Dual-PROTAC策略示意图细胞实验结果显示，所合成的双靶点PROTAC在SW1990和H1299细胞系中，能够同时实现对EGFR和PARP的降解，并且其降解效果呈现出浓度和时间的依赖性。此研究首次成功实现一个小分子同时降解两种不同靶蛋白，拓展了PROTAC技术应用并开辟药物发现新领域，然而该策略可能会由于分子量的增加，从而引发药物性质和药代动力学方面的一系列问题。 PART. 03 miRNA-触发DNA编码的前PROTAC平台 DNA具备可编程性，这一特性使其能够构建多种多样的纳米结构，进而为动态DNA纳米技术的开发奠定了基础。近期，南京大学张晶晶教授研究团队针对上述新型PROTAC策略的局限性，以miRNA触发的DNA编码的pre-PROTAC的形态调节为依据，成功开发出一种全新的miRNA启动的组装pre-PROTAC平台，即miRiaTAC。 miRiaTAC的模块化工具包含一对可修饰的DNA发夹H1和H2。在癌细胞中，靶miR -21呈现过表达的状态，H1和H2能够对其做出响应，并通过HCR形成交替共聚物。具体而言，弹头JQ-1（L1）标记的H1可以招募靶蛋白BRD4，而H2与配体pomalidomide（L2）结合以招募CRBN E3泛素连接酶。精确确定L1和L2的修饰位点，以确保在miR-21启动时L1/L2对的邻近性，使miRiaTAC诱导BRD4多泛素化，引起其蛋白酶体介导的降解，并形成（BRD4）m:miRiaTAC:(E3)n复合物（图6）。图6. 原位miRNA启动组装预protac（miRiaTAC）系统的示意图为了进一步降低过度降解所带来的副作用，研究人员设计了一种用于时空控制终止蛋白质降解的概念策略。他们通过在合适的位置插入可光性基团，实现了对长dsDNA纳米结构拆卸过程的光学调节，从而构建出一个具有理想可控性的系统。针对多重蛋白降解这一挑战，研究人员将另一种配体（L3）添加到H1上，以此来募集CDK6。借助可编程的配体比例，成功实现了正交多靶点降解（图7）。此外，体内实验也进一步证实了miRiaTAC在小鼠肿瘤模型中展现出强大的抗癌活性以及显著的肿瘤抑制效果。图7. miRiaTAC的多重蛋白降解模式 miRiaTAC策略通过插入光不稳定基团实现了对蛋白质降解的时空控制终止，避免了过度蛋白降解。同时，研究人员设计了一种新的DNA编码预PROTAC（H1-Pal），可实现单靶点和双靶点蛋白降解，拓宽了miRiaTAC在多靶点治疗中的应用。总之，miRiaTAC平台解决了传统PROTACs和miRNA疗法的关键挑战，为开发下一代靶向癌症治疗提供了有前景的途径。参考文献(可上下滑动）： [1]Zhang, Ni-Yuan et al. “Nano Proteolysis Targeting Chimeras (PROTACs) with Anti-Hook Effect for Tumor Therapy.” Angewandte Chemie (International ed. in English) vol. 62,37 (2023): e202308049. doi:10.1002/anie.202308049 [2]Jin, Yuhui et al. “Ligation to Scavenging Strategy Enables On-Demand Termination of Targeted Protein Degradation.” Journal of the American Chemical Society vol. 145,13 (2023): 7218-7229. doi:10.1021/jacs.2c12809 [3]Zhou, Li et al. “DNA framework-engineered chimeras platform enables selectively targeted protein degradation.” Nature communications vol. 14,1 4510. 27 Jul. 2023, doi:10.1038/s41467-023-40244-7 [4]Zheng, Mengzhu et al. “Rational Design and Synthesis of Novel Dual PROTACs for Simultaneous Degradation of EGFR and PARP.” Journal of medicinal chemistry vol. 64,11 (2021): 7839-7852. doi:10.1021/acs.jmedchem.1c00649 [5]Hollingsworth, S., Johnson, S., Khakbaz, P. et al. The rise of targeting chimeras (TACs): next-generation medicines that preempt cellular events. Med Chem Res 32, 1294–1314 (2023). https://doi-org.libproxy1.nus.edu.sg/10.1007/s00044-023-03104-z [6]Zhan, Jiayin et al. “MicroRNA-Triggered Programmable DNA-Encoded Pre-PROTACs for Cell-Selective and Controlled Protein Degradation.” Angewandte Chemie (International ed. in English), e202415323. 9 Oct. 2024, doi:10.1002/anie.202415323 *声明：本文仅是介绍医药疾病领域研究进展或简述研究概况或分享医药相关讯息，并非也不会进行治疗或诊断方案推荐，也不对相关投资构成任何建议。内容如有疏漏，欢迎沟通指出！「医药一哥」赴港二次上市传闻起，拟募资20亿美元，透露哪些信号？辉瑞DMD基因疗法折戟，试验结果“打脸”FDA 这5家核药公司，值得关注！

蛋白降解靶向嵌合体临床结果

2024-10-28

·药明康德

“癌症之王”患者6个月生存率超90%的KRAS靶向小分子；疾病控制率达100%的FGFR3靶向疗法…… | 一周盘点

▎药明康德内容团队编辑本期看点 1. 口服选择性FGFR3靶向疗法TYRA-300的早期临床结果亮眼，接受剂量≥90 mg/天的FGFR3突变转移性尿路上皮癌（mUC）患者的疾病控制率（DCR）为100%。 2. 泛RAS抑制剂RMC-6236在经治胰腺导管腺癌（PDAC）患者中展现出令人鼓舞的抗肿瘤活性和安全性，携带任意RAS突变的PDAC患者在6个月的总生存率为91%。 3. 治疗转移性透明细胞肾细胞癌（ccRCC）的小分子HIF-2a抑制剂casdatifan在一项1/1b期临床试验中的DCR达81%。药明康德内容团队整理 TYRA-300：公布1/2期临床试验数据 Tyra Biosciences公司公布了其潜在“first-in-class”的口服疗法TYRA-300治疗转移性尿路上皮癌（mUC）患者的1/2期研究SURF301的数据。TYRA-300是一种FGFR3选择性抑制剂，旨在避免抑制FGFR1、FGFR2和FGFR4时产生的毒性，且无论是否存在与耐药性相关的FGFR3门卫（gatekeeper）突变都能发挥作用。截至2024年8月15日的数据，接受剂量≥90 mg/天的FGFR3突变mUC患者的DCR为100%，54.5%（6/11）的患者达到部分缓解（PR），其中3例仍在治疗中，接受90 mg/天剂量的患者中有50%（5/10）达到PR。安全性方面，TYRA-300的耐受性总体良好，FGFR2和FGFR1相关毒性不常见。 RMC-6236：公布1/1b期临床试验数据 Revolution Medicines公司宣布，其在研泛RAS抑制剂RMC-6236在经治胰腺导管腺癌患者中展现出令人鼓舞的抗肿瘤活性和安全性。RMC-6236是一款口服、可靶向突变和野生型RAS在GTP结合（具活性，ON）状态下的选择性抑制剂。此次公布的1/1b期多中心、开放标签、剂量递增和剂量扩展研究RMC-6236-001旨在评估RMC-6236作为单药治疗携带RAS突变或野生型RAS晚期实体瘤患者的效果。结果显示，RMC-6236单药作为二线疗法可改善携带任意RAS突变PDAC患者的中位无进展生存期（PFS）与总生存期（OS）。在二线治疗中，携带KRAS G12X突变（KRAS G12X指的是KRAS蛋白第12位的甘氨酸因为基因突变，转换成其它氨基酸）的PDAC患者的中位PFS为8.5个月，中位OS为14.5个月。携带任意RAS突变的PDAC患者在二线治疗中的中位PFS为7.6个月，中位OS为14.5个月。携带KRAS G12X突变与携带任意RAS突变的PDAC患者在6个月时的总生存率分别为89%与91%。在二线治疗组中，携带KRAS G12X突变患者的客观缓解率（ORR）为29%，在三线及以上治疗组（3L+）中为22%，这些患者的DCR分别为91%和89%。目前该疗法的3期临床试验RASolute 302正在进行中。 Casdatifan：公布1/1b期临床试验数据 Arcus Biosciences公司公布了其在研小分子HIF-2a抑制剂casdatifan治疗转移性透明细胞肾细胞癌的1/1b期临床试验数据。HIF-2a是一种致癌转录因子，参与多个器官和肿瘤中的氧感应。由于VHL通路的基因异常，ccRCC几乎普遍与HIF-2a失调有关。通过选择性抑制HIF-2a，casdatifan可使一系列涉及肿瘤增殖和存活、耐药性和血管生成的通路失效，从而导致癌细胞死亡。截至2024年8月30日的数据，中位随访时间为11个月。在100 mg每日剂量扩展队列（n=32）中，DCR达81%，ORR为34%（2个待确认的缓解），许多患者仍在接受治疗。安全性方面，casdatifan具有可接受且可管理的安全性。 ▲Casdatifan治疗ccRCC患者的1/1b期试验数据（图片来源：参考资料[7]） NX-5948：公布1a/1b期临床试验数据 Nurix Therapeutics公司公布其在研蛋白降解剂NX-5948在治疗复发/难治性华氏巨球蛋白血症（WM）患者的1a/1b期临床试验中的最新数据。NX-5948是一种口服、可穿越血脑屏障的小分子布鲁顿氏酪氨酸激酶（BTK）蛋白降解剂。Nurix此前报告称，NX-5948对一系列对现有BTK抑制剂耐药的肿瘤细胞系表现出高效的抑制活性，这对于经过大量前期治疗的B细胞恶性肿瘤患者群体尤为重要。截至2024年10月10日的数据，在9例可评估应答的患者中，7例患者（77.8%）出现客观缓解，两例患者病情稳定（22.2%）。所有7例缓解均在8周的首次评估中观察到，其中5例患者仍在接受治疗，2例患者的治疗时间超过一年。不论患者基线MYD88和CXCR4的突变状态如何，均观察到应答。 Bel-sar（AU-011）：公布1期临床试验数据 Aura Biosciences公司宣布，其在研病毒样偶联药物（VDC）bel-sar（AU-011）在治疗非肌层浸润性膀胱癌（NMIBC）患者的1期临床试验中获得积极早期数据。Bel-sar由靶向肿瘤表面表达的糖蛋白的类病毒颗粒（VLP）与可由光激活的细胞毒性药物偶联生成。它被设计为具有双重作用机制，既能诱导肿瘤细胞坏死，又能激发强大且持久的抗肿瘤免疫反应。该试验共纳入了13名患者，主要终点是评估bel-sar单独使用（n=5）和bel-sar结合光激活（n=8）局部给药的安全性和可行性。次要终点是评估生物活性及肿瘤微环境（TME）中的免疫介导变化。13名研究参与者中，10名为低级别疾病患者，另外3名为高级别疾病患者。在接受bel-sar结合光激活治疗的患者（n=8）中，5名低级别疾病患者中有4名在组织病理学评估中显示无肿瘤细胞残留，达到了临床完全缓解（CR）。3名高级别疾病患者中有2名在膀胱镜检查中显示肿瘤明显缩小。 ONCT-534：公布1/2期临床试验数据 Oncternal Therapeutics公司公布了其在研雄激素受体（AR）抑制剂ONCT-534治疗复发性或难治性转移性去势抵抗性前列腺癌（mCRPC）患者的1/2期研究的最新数据。ONCT-534在前列腺癌模型中对未发生突变的AR以及多种形式的AR突变和异常都具有活性。ONCT-534具有治疗对AR通路抑制剂耐药（包括AR扩增、AR配体结合域突变或AR配体结合域缺失型剪接变体）的mCRPC患者的潜力。截至2024年9月30日的数据，每天两次的给药方案耐受性良好，没有出现与治疗相关的3级或更高级别的毒性反应。1名患者在接受每日两次160 mg剂量ONCT-534治疗后，前列腺特异性抗原（PSA）升高，但在随后4周以每日两次300 mg剂量ONCT-534治疗后，PSA下降了50%，同时计算机断层扫描（CT）显示与基线相比，靶病灶减少了16%。循环肿瘤细胞（CTCs）的计数和生物标志物分析显示，在另外6名患者中，ONCT-534对AR调控基因的表达和AR的核转位有令人鼓舞的效果。 Lunresertib+camonsertib：公布1期联合治疗试验数据 Repare Therapeutics公司公布了1期临床试验MYTHIC的最新数据，该试验评估了其PKMYT1抑制剂lunresertib和口服小分子ATR抑制剂camonsertib（lunre+camo）的组合疗法。在这项分析中，Repare公司对接受2期段推荐剂量（RP2D）的患者进行了约9个月的随访。结果显示，lunre+camo在保持临床疗效的同时，成功地减轻了与抗肿瘤药物机制相关的贫血。此外，在这些患者中未观察到任何级别的血小板减少或严重的中性粒细胞减少。 ATX-559：IND申请获得FDA许可 Accent Therapeutics公司宣布美国FDA已批准其潜在“first-in-class”的DHX9抑制剂ATX-559的IND申请，可在实体瘤患者中开展1期研究，重点关注BRCA1/2缺陷的乳腺癌和微卫星不稳定性高（MSI-H）和/或错配修复缺陷（dMMR）的实体瘤，预计首例患者将在2024年第四季度接受给药。 DHX9是一种DNA/RNA螺旋酶，据报道在复制、转录、翻译、RNA剪接、RNA处理以及维持基因稳定性等方面发挥着重要作用，该酶是一个有吸引力的新肿瘤学靶点。ATX-559通过抑制DHX9可利用关键的肿瘤弱点，导致癌症特异性细胞死亡。 ▲欲了解更多前沿技术在生物医药产业中的应用，请长按扫描上方二维码，即可访问“药明直播间”，观看相关话题的直播讨论与精彩回放参考资料（可上下滑动查看） [1] Revolution Medicines Presents Updated Data from RMC-6236 Monotherapy Study in Patients with Advanced Pancreatic Ductal Adenocarcinoma. Retrieved October 23, 2024 from https://www.globenewswire.com/en/news-release/2024/10/23/2967583/0/en/Revolution-Medicines-Presents-Updated-Data-from-RMC-6236-Monotherapy-Study-in-Patients-with-Advanced-Pancreatic-Ductal-Adenocarcinoma.html [2] Multiple Clinical Complete Responses Demonstrated Following Single Low Dose Administration of Bel-sar in Patients with Non-Muscle-Invasive Bladder Cancer (NMIBC) in Ongoing Phase 1 Trial. Retrieved October 18, 2024, from https://ir.aurabiosciences.com/news-releases/news-release-details/multiple-clinical-complete-responses-demonstrated-following [3] Oncternal Therapeutics Announces Updated Safety and Efficacy Data for Phase 1/2 Study of ONCT-534 for the Treatment of R/R Metastatic Castration-Resistant Prostate Cancer. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/22/2967000/0/en/Oncternal-Therapeutics-Announces-Updated-Safety-and-Efficacy-Data-for-Phase-1-2-Study-of-ONCT-534-for-the-Treatment-of-R-R-Metastatic-Castration-Resistant-Prostate-Cancer.html [4] Nurix Therapeutics Presents Positive Results from the Ongoing Clinical Trial of Its BTK Degrader NX-5948 in Patients with Relapsed/Refractory Waldenstrom’s Macroglobulinemia. Retrieved October 21, 2024, from https://www.globenewswire.com/en/news-release/2024/10/19/2965795/0/en/Nurix-Therapeutics-Presents-Positive-Results-from-the-Ongoing-Clinical-Trial-of-Its-BTK-Degrader-NX-5948-in-Patients-with-Relapsed-Refractory-Waldenstrom-s-Macroglobulinemia.html [5] Repare Therapeutics Announces Updated Positive Safety and Tolerability Results from the Phase 1 MYTHIC Clinical Trial. Retrieved October 25, 2024, from https://ir.reparerx.com/news-releases/news-release-details/repare-therapeutics-announces-updated-positive-safety-and [6] Tyra Biosciences Reports Interim Clinical Proof-of-Concept Data for TYRA-300, an Investigational Oral FGFR3-Selective Inhibitor, in Phase 1/2 SURF301 Study in Patients with Metastatic Urothelial Cancer (mUC). Retrieved October 25, 2024, from https://www.callunapharma.com/wp-content/uploads/2024/01/Calluna_Pharma_Launch_PR.pdf [7] First Clinical Data for Arcus Biosciences’ HIF-2a Inhibitor, Casdatifan, Showed Promising Clinical Activity and Tumor Shrinkage in Patients with Metastatic Kidney Cancer. Retrieved October 25, 2024, from https://investors.arcusbio.com/investors-and-media/press-releases/press-release-details/2024/First-Clinical-Data-for-Arcus-Biosciences-HIF-2a-Inhibitor-Casdatifan-Showed-Promising-Clinical-Activity-and-Tumor-Shrinkage-in-Patients-with-Metastatic-Kidney-Cancer/default.aspx [8] Interius BioTherapeutics Doses First Patient with in vivo Chimeric Antigen Receptor (CAR) Gene Therapy for B-cell Malignancies. Retrieved October 25, 2024, from https://interiusbio.com/2024/10/interius-biotherapeutics-doses-first-patient-with-in-vivo-chimeric-antigen-receptor-car-gene-therapy-for-b-cell-malignancies/ [9] Spur Therapeutics Showcases Positive New Data from Phase 1/2 GALILEO-1 Trial of FLT201, Its Novel Gene Therapy Candidate for Gaucher Disease, in Oral Presentation at ESGCT 31st Annual Congress. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/23/2967469/0/en/Spur-Therapeutics-Showcases-Positive-New-Data-from-Phase-1-2-GALILEO-1-Trial-of-FLT201-Its-Novel-Gene-Therapy-Candidate-for-Gaucher-Disease-in-Oral-Presentation-at-ESGCT-31st-Annua.html [10] Find Therapeutics Announces First Subject Dosed in Phase 1 Clinical Study of FTX-101. Retrieved October 25, 2024, from https://www.prnewswire.com/news-releases/find-therapeutics-announces-first-subject-dosed-in-phase-1-clinical-study-of-ftx-101-302278520.html [11] Zymeworks Announces First Patient Dosed in Phase 1 Clinical Trial Evaluating ZW171 in Advanced Mesothelin-Expressing Cancers. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/21/2966023/0/en/Zymeworks-Announces-First-Patient-Dosed-in-Phase-1-Clinical-Trial-Evaluating-ZW171-in-Advanced-Mesothelin-Expressing-Cancers.html [12] Aligos Therapeutics Announces U.S. FDA Clearance of IND Application for ALG-000184. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/22/2966892/0/en/Aligos-Therapeutics-Announces-U-S-FDA-Clearance-of-IND-Application-for-ALG-000184.html [13] Pierre Fabre宣布在PFL-002/VERT-002的I/II期首次给药，这是一种MET改变的NSCLC靶向治疗. Retrieved October 25, 2024, from https://www.prnasia.com/story/465694-1.shtml [14] Inozyme Pharma Announces Positive Interim Data from Phase 1 SEAPORT 1 Trial of INZ-701. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/24/2968997/0/en/Inozyme-Pharma-Announces-Positive-Interim-Data-from-Phase-1-SEAPORT-1-Trial-of-INZ-701.html [15] Apogee Therapeutics Announces Results Up to 9 Months from Phase 1 Trial of APG777, its Novel Half-Life Extended Anti-IL-13 Antibody for the Treatment for Atopic Dermatitis and Other Inflammatory Diseases. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/24/2968646/0/en/Apogee-Therapeutics-Announces-Results-Up-to-9-Months-from-Phase-1-Trial-of-APG777-its-Novel-Half-Life-Extended-Anti-IL-13-Antibody-for-the-Treatment-for-Atopic-Dermatitis-and-Other.html [16] BridgeBio Shares Positive Data from High Dose Cohort of Phase 1/2 CANaspire Study of Gene Therapy BBP-812 for Canavan Disease at ESGCT 2024. Retrieved October 25, 2024, from https://www.globenewswire.com/news-release/2024/10/24/2968601/0/en/BridgeBio-Shares-Positive-Data-from-High-Dose-Cohort-of-Phase-1-2-CANaspire-Study-of-Gene-Therapy-BBP-812-for-Canavan-Disease-at-ESGCT-2024.html [17] Precision BioSciences Receives First Approval of Clinical Trial Application to Initiate PBGENE-HBV First-In-Human Study for the Treatment of Chronic Hepatitis B. Retrieved October 25, 2024, from https://investor.precisionbiosciences.com/news-releases/news-release-details/precision-biosciences-receives-first-approval-clinical-trial [18] First Patients Dosed in Phase 1 Clinical Study of ImmunityBio’s CAR-NK Cell Therapy for the Treatment of Relapsed B-Cell Non-Hodgkin Lymphoma. Retrieved October 25, 2024, from https://ir.immunitybio.com/news-releases/news-release-details/first-patients-dosed-phase-1-clinical-study-immunitybios-car-nk?field_nir_news_date_value[min]= [19] Aprea Therapeutics Presents Preliminary Findings on Oral WEE1 Inhibitor APR-1051 at EORTC-NCI-AACR International Conference on Molecular Targets and Therapeutics. Retrieved October 25, 2024, from https://ir.aprea.com/news-releases/news-release-details/aprea-therapeutics-presents-preliminary-findings-oral-wee1 [20] Autolus Therapeutics Presents Clinical Data Update at the 2024 Lymphoma, Leukemia & Myeloma Congress. Retrieved October 25, 2024, from　https://www.globenewswire.com/news-release/2024/10/16/2964125/0/en/Autolus-Therapeutics-Presents-Clinical-Data-Update-at-the-2024-Lymphoma-Leukemia-Myeloma-Congress.html [21] Accent Therapeutics Announces FDA Clearance of IND Application for ATX-559, a First-In-Class Oral DHX9 Inhibitor. Retrieved October 25, 2024, from　https://www.prnewswire.com/news-releases/accent-therapeutics-announces-fda-clearance-of-ind-application-for-atx-559-a-first-in-class-oral-dhx9-inhibitor-302285845.html [22] Calluna Pharma launches and announces EUR 75 million Series A financing to develop novel therapies for inflammatory and fibrotic diseases. Retrieved October 25, 2024, from　 https://www.businesswire.com/news/home/20241023939388/en/Calluna-Pharma-Successfully-Completes-Phase-1-Clinical-Study-of-CAL101-a-First-in-Class-Therapeutic-for-Fibrotic-and-Fibro-Inflammatory-Indications/#:~:text=Calluna%20Pharma%20Successfully%20Completes%20Phase%201%20Clinical%20Study,CAL101%20is%20now%20entering%20Phase%202%20clinical%20development 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。版权说明：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「药明康德」微信公众号回复“转载”，获取转载须知。分享，点赞，在看，聚焦全球生物医药健康创新

临床结果基因疗法临床终止