奥拉帕利(Olaparib) - 药物靶点：PARP1 x PARP2 x PARP3_在研适应症：晚期子宫内膜癌，复发性子宫内膜癌，BRCA突变阳性乳腺癌_专利_临床

概要

基本信息

药物类型

小分子化药

别名

4-(3-{[4-(cyclopropylcarbonyl)piperazin-1-yl]carbonyl}-4-fluorobenzyl)phthalazin-1(2H)-one、Olaparib (JAN/USAN/INN)、奥拉帕尼

+ [14]

靶点

PARP1 x PARP2 x PARP3

作用方式

抑制剂

作用机制

PARP1抑制剂(聚腺苷二磷酸核糖聚合酶1抑制剂)、PARP2抑制剂(聚腺苷二磷酸核糖聚合酶2抑制剂)、PARP3抑制剂(聚腺苷二磷酸核糖聚合酶3抑制剂)

治疗领域

肿瘤消化系统疾病内分泌与代谢疾病+ [9]

在研适应症

晚期子宫内膜癌复发性子宫内膜癌BRCA突变阳性乳腺癌+ [128]

非在研适应症

晚期癌症晚期宫颈癌晚期胃癌+ [44]

原研机构

AstraZeneca PLC

在研机构

AstraZeneca PLC

Merck Sharp & Dohme Corp.

阿斯利康制药有限公司

+ [14]

非在研机构

Novartis Pharmaceuticals Corp.

Advanced Accelerator Applications SA

Sandoz Group AG

+ [2]

权益机构

Merck & Co., Inc.

AstraZeneca PLC

Breast International Group

+ [1]

最高研发阶段批准上市

首次获批日期

欧盟 (2014-12-16),

BRCA突变去势抵抗性前列腺癌BRCA突变输卵管癌BRCA 突变卵巢癌+ [12]

最高研发阶段(中国)批准上市

特殊审评快速通道 (美国)、加速批准 (美国)、孤儿药 (美国)、孤儿药 (日本)、加速批准 (加拿大)、优先审评 (澳大利亚)、优先审评 (美国)、附条件批准 (中国)、优先审评 (中国)、特殊审批 (中国)、突破性疗法 (美国)

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结构/序列

分子式C24H23FN4O3

InChIKeyFDLYAMZZIXQODN-UHFFFAOYSA-N

CAS号763113-22-0

关联

532

项与奥拉帕利相关的临床试验

NCT07850973

/ Not yet recruiting临床1/2期

Phase 1/2 Study Of PARP Inhibition With Olaparib To Enhance The Efficacy Of High-Dose Chemotherapy In Refractory And Relapsed Germ Cell Tumors

The goal of this clinical research study is to find the highest safe dose of olaparib that can be combined with chemotherapy drugs and stem cell transplantation to treat patients with relapsed and refractory germ cell cancer. The safety and effectiveness of this treatment combination therapies will also be studied.

开始日期2027-03-01

申办/合作机构-

NCT07933419

/ Not yet recruiting临床1/2期

A Phase Ib/II Clinical Study on the Safety, Tolerability, Pharmacokinetics, and Efficacy of Intravenous QLS5133 Combination Therapy in Participants With Advanced Solid Tumors

The goal of this clinical trial is to evaluate the safety, tolerability, pharmacokinetics (PK), and effectiveness of the investigational drug QLS5133 (injectable) in combination with other therapies for participants with advanced solid tumors. This is a multicenter, open-label study consisting of two parts: dose escalation and tumor-specific expansion.
The main questions it aims to answer are:
* In the dose-escalation part: What is the safety, tolerability, PK profile, and preliminary efficacy of QLS5133 combination therapy, and what are the recommended dose(s) for expansion?
* In the expansion part: What is the anti-tumor efficacy and further safety profile of QLS5133 combination therapy at the selected dose(s) in participants with specific tumor types?
Participants will:
* Be enrolled in sequential cohorts to receive QLS5133 in combination with other anticancer agents.
* Undergo regular assessments for safety, drug concentration levels (PK), and tumor response.

开始日期2026-11-15

申办/合作机构

齐鲁制药有限公司

CTRI/2026/09/117590

/ Not yet recruiting临床2期IIT

A Dose Optimization Study of Olaparib in Ovarian Cancer Patients - NIL

开始日期2026-10-15

申办/合作机构-

100 项与奥拉帕利相关的临床结果

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100 项与奥拉帕利相关的转化医学

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100 项与奥拉帕利相关的专利（医药）

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4,815

项与奥拉帕利相关的文献（医药）

2027-01-01·CANCER LETTERS

SAGE1-mediated H3K27ac enrichment promotes chromatin opening and Fanconi Anemia repair to induce carboplatin resistance in triple-negative breast cancer

Article

作者: Gao, Weiqi ; Pan, Ruixin ; Shen, Kunwei ; Wang, Shaodong ; Wang, Zheng ; Dong, Shuwen ; Huang, Renhong

Platinum-based chemotherapy is a cornerstone of triple-negative breast cancer (TNBC) treatment, yet resistance remains a significant clinical challenge. Sarcoma antigen 1 (SAGE1), a cancer-testis antigen, has been implicated in various malignancies, but its specific role in TNBC drug response and underlying mechanisms remain largely elusive. Using tumor specimens from two prospective TNBC trials, we found that high SAGE1 expression significantly correlates with inferior invasive disease-free survival in patients receiving carboplatin-containing chemotherapy. SAGE1 reduces carboplatin sensitivity in vitro and in vivo by accelerating DNA damage repair. Mechanistically, SAGE1 enhances global chromatin accessibility and H3K27ac enrichment at Fanconi Anemia (FA) pathway gene loci, interacting with p300 and BRD4 to promote H3K27ac deposition. The BET bromodomain inhibitor JQ1 reversed FA protein upregulation and restored carboplatin sensitivity in SAGE1-enriched cells. Furthermore, SAGE1 interacts with PARP1, and this interaction is associated with the regulation of PARP1 activity and with limited PARP inhibitor sensitivity. Notably, the triple combination of JQ1, carboplatin, and olaparib enhanced DNA damage and suppressed tumor growth in preclinical models. Thus, SAGE1 may contribute to an epigenetic-repair axis by facilitating chromatin opening and bolstering the FA pathway, and targeting this axis via combined carboplatin, PARP, and BET inhibition represents a promising therapeutic strategy for SAGE1-enriched TNBC.

2026-12-31·CANCER BIOLOGY & THERAPY

Evaluating carboplatin and PARP inhibitor combination efficacy using high-grade serous carcinoma spheroids and organoids

Article

作者: Tomas, Emily J. ; Davis, Jennifer ; Ramos Valdes, Yudith ; Shepherd, Trevor G.

BACKGROUND:

PARP inhibitors (PARPis) are new targeted agents that exploit homologous recombination DNA repair deficiencies (HRDs), which are present in 50% of high-grade serous carcinoma (HGSC) cases. Currently, olaparib is approved as maintenance therapy for BRCA1/2-mutated HGSC, and niraparib is approved for platinum-sensitive recurrent disease. However, research is currently expanding their potential as front-line agents or in combination with carboplatin, a standard HGSC chemotherapeutic.

METHODS:

Immortalized ovarian cancer (iOvCa) cell lines, developed from HGSC patient ascites, were treated with carboplatin, olaparib and niraparib to determine their sensitivity. Immunofluorescence analysis of RAD51 was conducted for HRD testing of all the cell lines. The cell lines were cultured as three-dimensional organoids and spheroids to mimic tumor growth and metastasis, respectively, and then treated to assess the effects of different drug combinations.

RESULTS:

The half-maximal inhibitory concentrations of olaparib and niraparib varied across our iOvCa cell lines, with iOvCa195 BRCA1-mutant line exhibiting the expected high sensitivity to both PARPis. Direct combination of carboplatin with olaparib or niraparib enhanced cell killing, yet achieved cell viability levels to those of carboplatin alone. In sequential experiments, carboplatin followed by either PARPi or vice versa showed no significant difference in cell viability to carboplatin alone, except in iOvCa195 organoids when treated with a PARPi first.

CONCLUSIONS:

Overall, first-line carboplatin treatment remains ideal, yet there may be select utility for PARPi prior to chemotherapy. Using patient-derived tumor models such as spheroids and organoids may provide insights for on-going and future clinical trials to enhance therapeutic outcomes for HGSC patients.

2026-12-01·NEUROPHARMACOLOGY

Proteasome-dependent degradation of DAPK1 by wogonoside blocks PARthanatos and protects against ischemic stroke

Article

作者: Liu, Zhi-Peng ; Zhang, Zhao-Huan ; Yu, Jin-Liu ; Xu, Xiao-Hui ; Shen, Yu-Xin ; Liu, Fang ; Cao, Yin ; Zhai, Chun-Ze ; Wang, Yi-Zhe ; Wang, Xiu-Xiu

Ischemic stroke remains a leading cause of death and disability, yet effective pharmacological neuroprotection remains elusive. ROS-induced PARthanatos-driven by PARP1 hyperactivation and the mitochondrial-apoptosis-inducing factor (AIF) death axis-is a principal executor of ischemic neuronal death. However, direct PARP1 inhibition inevitably compromises essential DNA repair. Here, we identify a downstream intervention node that uncouples lethal signaling from genomic maintenance. Through phenotype-to-target deconvolution combining reverse pharmacophore mapping, bioinformatic intersection with programmed cell death genes, and integrated biophysical validation (docking, 100-ns molecular dynamics, cellular thermal shift assay, and surface plasmon resonance), we demonstrate that wogonoside (WS), a flavonoid glycoside from Scutellaria baicalensis, directly binds death-associated protein kinase 1 (DAPK1; KD = 6.07 μM) and acts as a ligand-induced degrader that triggers proteasome-dependent DAPK1 clearance. CRISPR/Cas9-mediated DAPK1 knockout fully phenocopied WS-mediated protection, whereas ectopic DAPK1 overexpression abolished it. WS-induced degradation intercepted the JNK-mitochondrial depolarization-AIF nuclear translocation cascade while leaving PARP1 catalytic activity, PAR polymer formation, and γH2AX resolution fully intact-in stark contrast to the clinical PARP1 inhibitor olaparib. In a mouse permanent distal middle cerebral artery occlusion model, a single dose of WS reduced cortical infarct volume by ∼50%, preserved neurons, suppressed microglial activation, and maintained microvascular integrity, accompanied by significant sensorimotor recovery. Single-nucleus RNA sequencing revealed Dapk1 enrichment in activated microglia and co-variation with neuronal MAPK pro-death signaling, suggesting a dual-compartment mechanism. These findings define proteasome-dependent DAPK1 degradation as a mechanistically distinct antioxidant strategy for acute ischemic stroke.

2,663

项与奥拉帕利相关的新闻（医药）

2026-11-13

·生物谷

前列腺癌还在“潜伏”，免疫系统已经提前上班了！Nature Communications：确诊前七年，IL-15越高，风险越低14%；晚期风险低26%

这项研究表明免疫系统可能在前列腺癌变得可检测之前很久就发挥着重要预防作用，免疫系统与较低癌症风险之间的联系，为人体如何控制新出现的癌细胞提供了线索。前列腺癌是英国男性中最常见的癌症，而诸如年龄、种族、家族史和遗传等已知风险因素没有一个是可以改变的，正因如此，预防策略长期缺位，医学界能做的多是等待诊断后再治疗。但近日，一篇发表在国际杂志Nature Communications上题为“Prospective and genetic analyses implicate lower immunosurveillance in the aetiology of prostate cancer”的研究报告中，来自牛津大学的研究人员通过研究发现，人体免疫系统或许在癌症被检出之前很多年，就已经在暗中左右着疾病的走向。这项研究是迄今规模最大、最全面的关于循环免疫与炎症相关蛋白和前列腺癌风险的前瞻性及遗传学分析。文章中，研究人员分析了来自欧洲癌症与营养前瞻性调查（EPIC）的血液样本，检测368种免疫和炎症相关蛋白，比较了1434名后来罹患前列腺癌的男性与1434名条件相似的对照男性，其中病例确诊平均在采血十余年之后。他们还将这些结果与英国生物银行的数据结合，后者纳入21481名男性参与者，含1147例前列腺癌病例，并借助遗传学方法判断蛋白与前列腺癌之间的关联是否可能具有因果性。研究者指出，在EPIC队列单独分析中，经多重检验校正后，没有任何蛋白与风险显著相关；但荟萃分析识别出若干与前列腺癌风险相关的蛋白，其中IL15和FLT3LG尤为突出，且信号在诊断前很久采集的血液中即已存在。总体而言，免疫监视相关蛋白水平较高—尤其是参与自然杀伤细胞和T细胞活动的蛋白—与较低的前列腺癌风险相关；而遗传学证据则提示PARP1、SPINT2和NME3与风险升高有关，这些发现表明，免疫通路在前列腺癌发生中扮演角色，并提示了潜在的预防靶点。观察性研究设计与遗传分析概述具体来看，最有力的发现之一围绕白细胞介素-15（IL-15），这种蛋白有助于刺激和维持抗癌的T细胞与自然杀伤细胞。在合并分析中，IL-15水平较高与七年后确诊前列腺癌的风险降低14%相关。在可获得肿瘤特征信息的EPIC队列中，较高的IL-15还与晚期前列腺癌风险降低26%相关。此外，FLT3LG、BCL2L11、PGF、CKAP4和TNFRSF11A水平较高，各自与采血七年多后前列腺癌风险降低相关。 Mahboubeh Parsaeian博士指出，前列腺癌曾被视为免疫学上的“冷”肿瘤，不太容易触发强烈免疫反应，但人们通常在肿瘤已经形成后才去研究免疫系统。这项研究的发现表明，免疫系统确实在前列腺癌的早期发生或抑制中发挥作用。她同时坦言，这些关联无法让人完整理解背后的生物学机制，但提示现有那些调控这些通路的药物，或许能在男性仍然健康时进行干预，而非等到确诊后再治疗。该研究还识别出另一条潜在预防路径，涉及DNA修复蛋白PARP1。利用遗传数据，研究者发现，遗传上倾向于具有较高PARP1水平的男性，前列腺癌风险升高，这一发现在一个独立的多族裔队列中得到重复。奥拉帕利等PARP抑制剂目前用于治疗部分前列腺癌，尤其是存在BRCA1或BRCA2等DNA修复通路缺陷的肿瘤，但尚未用于癌症预防。这项研究中引人注目的是，最强的免疫信号出现在诊断七年多之前，指向一个更早的时期，免疫系统可能正在帮助控制异常细胞。IL-15尤其值得关注，因为它支持自然杀伤细胞和杀伤性T细胞，而这些正是人们预期会参与此类异常细胞监视的细胞。PARP1的发现则提出一种引人注目的可能：一个在前列腺癌发生后已被靶向的通路，或许也影响疾病是否会发生。接下来研究人员将测试这些蛋白如何相互作用及影响它们能否改变风险，长远目标是通过前列腺癌病因与预防（PCAP）项目，把这些发现转化为预防癌症的方法。这项研究表明免疫系统可能在前列腺癌变得可检测之前很久就发挥着重要预防作用，免疫系统与较低癌症风险之间的联系，为人体如何控制新出现的癌细胞提供了线索。研究者Ruth Travis教授则表示，这些特征丰富的群体研究正在改变人们对癌症的理解，首次让人得以在确诊多年前审视疾病的生物学，通过分析数千种蛋白质，揭示影响谁患前列腺癌、谁不患的机制线索，有助于走向更有效的预防策略并识别干预可能收效最大的关键窗口期。（生物谷Bioon.com）参考文献： Parsaeian, M., Chan, W.C., Atkins, J.R. et al. Prospective and genetic analyses implicate lower immunosurveillance in the aetiology of prostate cancer. Nat Commun 17, 10698 (2026). doi：10.1038/s41467-026-77378-3

2026-11-12

·ioncology

瞭望ESMO丨胆道肿瘤晚期维持与围手术期新辅助的前沿线索

点击蓝字关注我们编者按胆道肿瘤恶性程度高，异质性强，晚期患者预后差，临床治疗仍存在诸多未被满足的需求。含铂化疗仍是晚期胆道癌一线标准方案，但一线疾病控制后尚无公认有效的维持治疗手段；而对于可切除肝内胆管癌，单纯手术术后复发率居高不下，新辅助治疗策略仍有待突破。2026年欧洲肿瘤内科学会年会（ESMO）公布两项重要Ⅱ期研究：OPTIMUM研究（摘要号：LBA22）探索PARP抑制剂奥拉帕利±度伐利尤单抗在DDR基因突变晚期胆道癌的维持治疗价值；NeoTreme研究（摘要号：471P）评估吉西他滨联合顺铂基础上加用双免疫制剂用于肝内胆管癌新辅助治疗的可行性。本文梳理两项研究核心数据，以期为临床胆道肿瘤个体化治疗决策及后续研究设计提供参考与启示。研究一中文标题：OPTIMUM：一项随机Ⅱ期研究，评估奥拉帕利（Ola）联合或不联合度伐利尤单抗（Durva）维持治疗DDR基因突变型晚期胆道癌（aBTC）的疗效英文标题：OPTIMUM: A randomized phase 2 study of maintenance olaparib (Ola) with or without durvalumab (Durva) in DDR gene-mutated advanced biliary tract cancer (aBTC)讲者：Changhoon Yoo (Seoul, Republic of Korea, Songpa-gu)摘要号：LBA22 + 研究背景含铂化疗是aBTC患者的标准治疗方案；然而，目前尚无疾病控制后的维持治疗策略得到验证。aBTC患者存在DNA损伤修复（DDR）基因突变，PARP抑制剂维持治疗可能改善该人群的生存率。研究方法 OPTIMUM是一项随机、开放标签、非对照Ⅱ期临床试验。入组患者需满足：aBTC、ECOG PS评分为0~1分、携带至少1种预设的体细胞或胚系DDR基因突变；接受一线含铂方案治疗≥16周后疾病未发生进展。患者按1:1比例随机分至A组（奥拉帕利300 mg，每日2次+度伐利尤单抗1500 mg静脉输注，每4周1次）或B组（奥拉帕利300 mg，每日2次）。主要研究终点为全分析集（FAS）的6个月无进展生存（PFS）率；共需入组62例患者，以验证6个月PFS率由历史数据48.0%提升至69.3%（风险比HR=0.5；单侧α=0.05，检验效能80%）（图1）。图1. OPTIMUM研究设计研究结果 2022年4月至2026年2月，共入组63例患者，61例患者纳入FAS（A组32例；B组29例）。两组基线特征均衡。最常见DDR基因突变为ATM（34%）、BRCA2（25%）及BAP1（25%）。A组6个PFS率为62.5%（95%CI：46.8~74.7），B组为62.1%（95%CI：45.5~74.9）（图2）。FAS人群2年总生存率为40.1%（95%CI：28.0~51.9）（图3）。核心同源重组缺陷（cHRD）亚组（18例，占30%）的中位PFS（20.5个月 vs. 7.4个月，P=0.008）及OS（尚未达到 vs. 16.5个月，P=0.007）均显著优于其他亚组。研究治疗时ctDNA中较高的变异等位基因频率（VAF）与PFS和OS呈负相关。奥拉帕利联合或不联合度伐利尤单抗，未出现新的安全性信号。图2. PFS与OS 图3. FAS人群的探索性生存分析研究结论本研究结果提示，cHRD定义的DDR突变aBTC，可从PARP抑制剂维持治疗中获得持久获益，支持进一步开发针对aBTC的HRD靶向治疗方案[1]。研究二中文标题：吉西他滨联合顺铂、度伐利尤单抗（MEDI4736）和曲麦利尤单抗治疗肝内胆管癌的Ⅱ期研究（NeoTreme）英文标题：Phase 2 study of preoperative gemcitabine plus cisplatin with durvalumab (MEDI4736) and tremelimumab in intrahepatic cholangiocarcinoma (NeoTreme) 讲者：Markus Moehler (Mainz, Germany) 摘要号：471P + 研究背景手术切除是肝内胆管癌（iCCA）根治性治疗的金标准。然而，尽管辅助治疗策略不断优化，大多数患者仍会出现快速复发。近年来，免疫联合疗法的出现为术前全身治疗提供了一种有前景的策略。研究方法本研究为一项前瞻性、多中心、单臂、Ⅱ期可行性临床试验，入组经组织学确诊、适合接受手术切除的初治iCCA患者。患者在手术切除前接受新辅助化疗联合免疫治疗（吉西他滨1000 mg/m2，顺铂25 mg/m2，于每周期第1、8天给药；度伐利尤单抗1500 mg，于21天周期的第1天给药；以及在第一个周期的第1天单次给予曲麦利尤单抗300 mg），共三个周期。主要终点为R0/R1切除率（图4）。本文报告所有接受至少1剂研究药物的入组患者的中期分析数据。图4. 研究设计研究结果共有31例患者接受了至少一剂研究药物。研究人群包括18例女性（58%）和13例男性（42%），中位年龄为62岁（四分位间距IQR，56~74岁）。所有患者的中位随访时间为173天（IQR，146~182天）。共有27例患者接受根治性手术切除，其中26例（84%）达到R0/R1切除（图5）。所有患者均发生至少1起不良事件。共有8例患者（26%）发生16起治疗相关严重不良事件，包括中性粒细胞减少伴发热（4例）、感染/脓毒症（3例）、腹泻（2例）、免疫相关性结肠炎（2例）、免疫相关性肝炎（2例）、免疫相关性心肌炎（1例）和免疫相关性后葡萄膜炎（1例）。图5. 研究结果研究结论对于iCCA，手术切除前采用吉西他滨、顺铂、度伐利尤单抗和曲麦利尤单抗进行新辅助化疗免疫治疗，值得在后续的随机对照Ⅱb/Ⅲ期试验中进行进一步研究[2]。参考文献：[1] Changhoon Yoo, et al. 2026 ESMO. Abstract LBA22.[2] Markus Moehler , et al. Lancet. 2026 ESMO. Abstract 471P. LBA22摘要原文：（上下滑动可查看） OPTIMUM: A randomized phase 2 study of maintenance olaparib (Ola) with or without durvalumab (Durva) in DDR gene-mutated advanced biliary tract cancer (aBTC) BACKGROUND: Platinum-containing therapy is standard of care for pts with aBTC; however, no maintenance strategy has been validated following disease control. DNA damage repair (DDR) gene mutations are identified in pts with aBTC and PARP inhibitor maintenance may improve survival in this population. METHODS: OPTIMUM is a randomized, open-label, non-comparative, phase 2 trial. Eligible pts had aBTC, ECOG PS 0–1, at least one predefined somatic or germline DDR gene mutation, and no disease progression after ≥16 weeks of 1L platinum-based therapy. Pts were randomized 1:1 to Arm A (Ola 300 mg BID + Durva 1,500 mg IV Q4W) or Arm B (Ola 300 mg BID). The primary endpoint was 6-month PFS rate in the Full Analysis Set (FAS), and 62 patients were required to detect its improvement from a historical 48.0% to 69.3% (HR 0.5; one-sided α=0.05, power 80%). RESULTS: Between April 2022 and February 2026, 63 pts were enrolled, and 61 pts were included in the FAS (Arm A: n=32; Arm B: n=29). Baseline characteristics were well balanced between arms. The most frequent DDR alterations were ATM (34%), BRCA2 (25%) and BAP1 (25%). The 6-month PFS rate was 62.5% (95% CI, 46.8–74.7) in Arm A and 62.1% (45.5–74.9) in Arm B. Two-year OS rate in overall FAS was 40.1% (28.0–51.9). The core homologous recombination deficiency (cHRD) group (n=18, 30%) was significantly associated with better median PFS (20.5 vs. 7.4 mo, P=0.008) and OS (not reached vs. 16.5 mo, P=0.007) compared to others. Higher VAF in ctDNA at the time of study treatment showed negative correlation with PFS and OS. There was no new safety profile of Ola +/- Durva. CONCLUSIONS: Our findings suggest that a cHRD-defined DDR-mutated aBTC derives durable benefit from PARP inhibitor maintenance, supporting further development of HRD-targeted therapy in aBTC. 471P摘要原文：（上下滑动可查看） Phase 2 study of preoperative gemcitabine plus cisplatin with durvalumab (MEDI4736) and tremelimumab in intrahepatic cholangiocarcinoma (NeoTreme) BACKGROUND: Surgical resection is the gold standard in curative stages of intrahepatic cholangiocarcinoma (iCCA). However, despite improved adjuvant strategies, rapid recurrence is observed in majority of patients. Recent advent in immunotherapy combinations supports the use of systemic treatment as a promising strategy in pre-operative settings. METHODS: This prospective, multicenter, single-arm, feasibility phase II trial was conducted for treatment-naïve patients with histologically confirmed iCCA eligible for surgical resection. Patients received neoadjuvant chemoimmunotherapy (gemcitabine 1000 mg/m2, cisplatin 25 mg/m2 on days 1 and 8 in combination with durvalumab 1500mg on days 1 of a 21-day cycle and a single dose of tremelimumab of 300mg on day 1 of first cycle) for a total of three cycles prior resection. Primary endpoint was rate of R0/R1 resections. Here presented data is an interim-analysis of all enrolled patients who received at least one dose of study medication. RESULTS: A total of 31 patients received at least one dose of study medication. Study population included 18 female (58%) and 13 male patients (42%) with a median age of 62 (IQR, 56–74). Median follow-up for all patients was 173 days (IQR, 146–182). Overall, 27 patients underwent curative-intent surgical resection with an R0/R1 resection in 26 patients (84%). All patients experienced at least one adverse event. Overall, 16 treatment-related serious adverse events occurred in 8 patients (26%) including neutropenic fever (4), infections/sepsis (3), diarrhea (2), immune-related (ir) colitis (2), ir-hepatitis (2), ir-myocarditis (1) and ir-posterior uveitis (1). CONCLUSIONS: Neoadjuvant chemoimmunotherapy with gemcitabine, cisplatin, durvalumab and tremelimumab prior to resection of intrahepatic cholangiocarcinoma warrants further investigation in a subsequent randomized controlled phase IIb/III trial. （来源：肿瘤瞭望消化时讯）声明凡署名原创的文章版权属《肿瘤瞭望》所有，欢迎分享、转载。本文仅供医疗卫生专业人士了解最新医药资讯参考使用，不代表本平台观点。该等信息不能以任何方式取代专业的医疗指导，也不应被视为诊疗建议，如果该信息被用于资讯以外的目的，本站及作者不承担相关责任。

临床2期临床结果

2026-11-11

·生物谷

Molecular Cell | 北京大学伊成器课题组揭示PARP1介导的m6A负反馈调控机制

N6-甲基腺苷（m6A）是哺乳动物mRNA中丰度最高且研究最多的一种修饰。这套修饰系统的秩序由三类蛋白维持：“书写器”（writer） METTL3/METTL14复合体负责加上修饰，“擦除器”（eraser）FTO/ALKBH5负责擦除修饰，“阅读器”（reader）如YTH家族蛋白和IGF2BP家族蛋白负责识别修饰并执行下游功能。m6A稳态的维持对于细胞多项生命活动至关重要。定量质谱结果显示，人体26种主要组织中总RNA 的m6A/A比值稳定在0.11%–0.23%之间。m6A一旦过多，会损害溶酶体功能、扰乱葡萄糖代谢；且异常升高的m6A与多种癌症的发生、转移密切相关。然而，m6A修饰水平与其eraser蛋白表达并不总是成负相关的，例如之前的研究发现，Fto敲除小鼠的大脑中，m6A图谱几乎不发生变化。因此，仅靠已知的writer/eraser/reader相互作用体系不足以解释m6A稳态，细胞中可能还存在另外一套调控系统。 2026年10月13日，北京大学伊成器课题组在Molecular Cell发表了题为A feedback mechanism of m6A via PARP1-mediated ADP ribosylation of METTL3/METTL14的研究论文，首次揭示了一条由PARP1介导的ADP核糖基化修饰参与m6A负反馈调控，并据此提出了PARP抑制剂联合m6A靶向抑制剂的肿瘤协同治疗新策略。研究团队结合226个RNA结合蛋白的CLIP-seq/RIP-seq数据与单碱基定量技术GLORI，并利用人工智能模型BioPathNet预测潜在互作因子，两条独立筛选结果均将PARP1排在前列。质谱和RIP-seq显示，细胞内PARP1结合的RNA显著富集m6A修饰，且偏好结合高m6A转录本及经典DRACH基序。但体外实验表明，纯化PARP1对m6A修饰与未修饰RNA的结合能力相近，提示PARP1并非直接识别m6A。进一步亲和纯化-质谱发现，PARP1同时与m6A阅读器IGF2BP1/2/3及书写器复合体METTL3/METTL14/WTAP相互作用。IGF2BP1和IGF2BP2凭借对m6A的高亲和力识别修饰RNA，并通过结合PARP1的ZnIII结构域将其招募至m6A位点。被募集的PARP1随后对METTL3/METTL14进行ADP核糖基化修饰，主要发生在METTL3的S2、K12和E20位点。AlphaFold3结构预测显示，S2位点的ADP-核糖占据辅因子SAM结合口袋，K12和E20位点修饰则占据RNA结合沟槽，从而显著削弱书写器复合体的RNA结合能力和催化效率。据此，研究提出“read–orchestrate–write”模型：m6A形成后，IGF2BP识别并招募PARP1至m6A-RNA；PARP1激活后抑制METTL3/METTL14，降低m6A生成，从而实现m6A稳态负反馈调控。该机制不依赖FTO，拓展了m6A稳态调控的经典框架。在肿瘤治疗层面，研究还发现长期使用奥拉帕利等PARP抑制剂会解除对书写器的抑制，使肿瘤细胞m6A水平升高。卵巢癌患者来源PDX模型显示，慢性奥拉帕利治疗后肿瘤m6A显著上升，升高位点富集于DNA损伤修复、细胞周期等耐药相关通路。联合阻断PAR修饰和m6A通路可产生协同抗肿瘤效应：PARP抑制剂联合IGF2BP2抑制剂可削弱高m6A RNA稳定性并促进其降解；PARP抑制剂联合METTL3抑制剂STM2457则直接抑制m6A生成。多株卵巢癌、乳腺癌细胞系及裸鼠成瘤、PDX模型均证实联合治疗具有显著协同杀伤作用，且该效应依赖完整PARP1信号。机制上，联合治疗通过加剧基因组不稳定性触发肿瘤细胞凋亡，并且不依赖BRCA1/2状态，有望扩大PARP抑制剂受益人群。图：PARP1介导的m6A负反馈调控机制自1963年PAR合成酶促反应被发现、1974年m6A修饰被鉴定以来，两项经典核酸修饰信号长期并行研究。该工作将ADP核糖基化信号转导与m6A表观转录组调控直接关联，提出RNA修饰领域首个负反馈调控机制，回答了“m6A稳态如何维持”的关键科学问题，并为克服PARP抑制剂耐药提供了新的联合治疗思路。北京大学生命科学学院、基因功能研究与操控全国重点实验室、核糖核酸北京研究中心、北大-清华生命科学联合中心伊成器教授为本文通讯作者，北京大学生命科学学院博士后白永泰博士为本文第一作者。本研究得到国家自然科学基金委员会、科技部、北大-清华生命科学联合中心、基因功能研究与操控全国重点实验室、核糖核酸北京研究中心以及新基石科学基金会等机构和项目的支持。论文链接： https://www.cell.com/molecular-cell/abstract/S1097-2765(26)00671-4 原文链接： https://www.bio.pku.edu.cn/homes/Index/news_cont/22/19188.html 本文仅用于学术分享，转载请注明出处。若有侵权，请联系微信：bioonSir 删除或修改！

100 项与奥拉帕利相关的药物交易

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KEGG	Wiki	ATC	Drug Bank
D09730	奥拉帕利	L01XK01	DB09074

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适应症	国家/地区	公司	日期
晚期子宫内膜癌	欧盟	AstraZeneca AB	2024-08-15
晚期子宫内膜癌	冰岛	AstraZeneca AB	2024-08-15
晚期子宫内膜癌	列支敦士登	AstraZeneca AB	2024-08-15
晚期子宫内膜癌	挪威	AstraZeneca AB	2024-08-15
复发性子宫内膜癌	欧盟	AstraZeneca AB	2024-08-15
复发性子宫内膜癌	冰岛	AstraZeneca AB	2024-08-15
复发性子宫内膜癌	列支敦士登	AstraZeneca AB	2024-08-15
复发性子宫内膜癌	挪威	AstraZeneca AB	2024-08-15
BRCA突变阳性乳腺癌	日本	AstraZeneca KK	2022-08-24
HRD 阳性卵巢癌	美国	AstraZeneca Pharmaceuticals LP	2020-05-19
HRR 基因突变去势抵抗性前列腺癌	美国	AstraZeneca Pharmaceuticals LP	2020-05-19
胰腺癌	韩国	AstraZeneca Pharmaceuticals LP	2019-10-29
前列腺癌	韩国	AstraZeneca Pharmaceuticals LP	2019-10-29
铂敏感性卵巢癌	中国	AstraZeneca AB	2018-08-22
复发性HER2阴性乳腺癌	日本	MSD KK (Tokyo)	2018-07-02
复发性HER2阴性乳腺癌	日本	AstraZeneca KK	2018-07-02
转移性胰腺腺癌	澳大利亚	AstraZeneca Pty Ltd.	2018-05-23
乳腺癌	加拿大	AstraZeneca Canada, Inc.	2016-04-29
卵巢癌	加拿大	AstraZeneca Canada, Inc.	2016-04-29
BRCA突变去势抵抗性前列腺癌	欧盟	AstraZeneca AB	2014-12-16

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适应症	最高研发状态	国家/地区	公司	日期
去势抵抗性前列腺癌	申请上市	美国	AstraZeneca PLC	2022-08-17
微卫星稳定型实体瘤	临床3期	西班牙	AstraZeneca PLC	2024-12-30
子宫内膜癌	临床3期	法国	AstraZeneca PLC	2024-06-26
子宫内膜样癌	临床3期	法国	AstraZeneca PLC	2024-06-26
卵巢浆液性腺癌	临床3期	美国	Novartis Pharmaceuticals Corp.	2021-07-22
卵巢浆液性腺癌	临床3期	中国	Novartis Pharmaceuticals Corp.	2021-07-22
卵巢浆液性腺癌	临床3期	阿根廷	Novartis Pharmaceuticals Corp.	2021-07-22
卵巢浆液性腺癌	临床3期	澳大利亚	Novartis Pharmaceuticals Corp.	2021-07-22
卵巢浆液性腺癌	临床3期	奥地利	Novartis Pharmaceuticals Corp.	2021-07-22
卵巢浆液性腺癌	临床3期	比利时	Novartis Pharmaceuticals Corp.	2021-07-22

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT03462342 (CAPRI, CTgov)	临床2期	复发性卵巢癌 \| 浆液性囊腺癌	127	platinum+olaparib+AZD6738 (Cohort A)	餘選築範鑰製夢製餘窪 = 範範獵繭餘鹽糧醖觸鹹觸鬱窪齋餘構蓋鏇壓壓 (繭襯簾憲壓觸艱觸網簾, 選鬱膚繭築鑰艱築範餘 ~ 艱遞糧衊鏇餘鹽醖獵窪) 更多	-	2026-11-10
				olaparib+AZD6738 (Cohort B)	餘選築範鑰製夢製餘窪 = 觸積選簾窪製願廠膚獵觸鬱窪齋餘構蓋鏇壓壓 (繭襯簾憲壓觸艱觸網簾, 鹽繭築遞餘憲築鹽憲觸 ~ 齋夢艱衊衊網鹽鬱鬱蓋) 更多
NCT04753879 (CTgov)	临床2期	转移性胰腺癌 \| 转移性胰腺导管腺癌	36	Olaparib+Nab-paclitaxel+Gemcitabine+Cisplatin+Pembrolizumab+Irinotecan+capecitabine	構範襯積築構積齋淵構 = 觸鬱構鹽鹽艱糧鹹醖壓醖糧鏇夢鏇糧蓋築鑰鏇 (遞觸艱繭鹽夢膚壓醖鹹, 顧憲獵夢壓淵艱築鹹蓋 ~ 繭鹽餘觸網觸鏇憲鏇憲) 更多	-	2026-11-04
NCT04643379 (CTgov)	临床2期	转移性头颈部鳞状细胞癌 \| 复发性头颈部鳞状细胞癌	30	Peripheral blood draw+Olaparib+Carboplatin+Pembrolizumab	獵膚遞製積製積簾繭構 = 顧鹽簾淵鹹襯鏇構襯鑰鑰範膚網遞鏇顧糧艱艱 (鏇顧窪遞膚遞壓獵觸艱, 衊遞製膚築觸鹽鹽膚鏇 ~ 鏇築築餘網窪願簾窪窪) 更多	-	2026-10-27
ESMO2026	N/A	HER2 阴性乳腺癌 BRCA1 \| BRCA2	52	Olaparib	簾選醖襯廠壓簾衊願壓(築襯顧觸鹹廠餘淵築憲) = included leukopenia (n=6), thrombocytopenia (n=2), nephropathy (n=1) and epigastric pain (n=1). 遞艱衊遞齋齋醖糧鹹選 (觸襯觸遞膚膚糧鬱鏇願 ) 更多	积极	2026-10-23
ESMO2026	N/A	转移性去势抵抗性前列腺癌一线	60	Olaparib + Abiraterone	繭積襯齋衊遞構遞襯鹽(蓋壓範遞築壓衊遞網鹽) = 衊淵繭鹹窪鹽顧簾壓鬱觸製繭鏇簾觸鏇顧夢遞 (簾齋簾構廠糧醖構願窪 ) 更多	积极	2026-10-23
				Docetaxel	積顧餘廠糧鹽顧艱鹹襯(夢窪餘襯鬱獵齋鏇糧製) = 鹽築壓築膚積鹽鹽鑰衊鏇繭網衊襯蓋蓋壓構觸 (糧淵鹹夢廠壓窪淵願衊 )
ESMO2026	N/A	转移性去势抵抗性前列腺癌 HRR	72	Olaparib + Abiraterone	淵顧夢膚夢窪鹹積艱鏇(鑰糧淵醖築製窪衊遞願) = 淵網膚觸選遞襯鹽簾範膚範觸齋鏇鏇範鹹網襯 (憲範蓋衊艱築憲夢鹽範 ) 更多	积极	2026-10-23
				Olaparib + Abiraterone (HRR alterations)	糧艱觸遞範繭鑰鹹構鹽(膚獵壓構選衊壓廠廠願) = 鹹膚觸廠製廠繭齋願觸醖鹽鏇窪憲鹽網鏇衊襯 (糧襯鑰遞網構廠壓選艱 )
NCT03317392 (COMRADE, ESMO2026)	临床2期	转移性去势抵抗性前列腺癌 AR \| TP53	232	Radium-223 + Olaparib	鏇淵齋餘獵淵鬱鑰鑰網(遞築遞願觸餘鏇窪醖繭) = 憲衊顧艱鹽積壓獵鏇壓壓衊淵蓋壓淵鏇蓋積膚 (觸顧襯淵選艱夢衊構窪 ) 更多	积极	2026-10-23
				Radium-223	鏇淵齋餘獵淵鬱鑰鑰網(遞築遞願觸餘鏇窪醖繭) = 醖遞選獵壓鹽廠鹽艱選壓衊淵蓋壓淵鏇蓋積膚 (觸顧襯淵選艱夢衊構窪 ) 更多
NCT03317392 (COMRADE, ESMO2026)	临床2期	转移性去势抵抗性前列腺癌 ctDNA tumor fraction (TF)	2,232	Olaparib + radium-223	積醖製齋餘膚構獵顧憲(衊築夢製鏇衊選選積蓋) = 獵構觸鬱淵鏇蓋鬱鑰鹽廠築鹹簾觸積顧窪範鹽 (衊獵淵鏇願構壓廠繭襯 ) 更多	积极	2026-10-23
				Radium-223	積醖製齋餘膚構獵顧憲(衊築夢製鏇衊選選積蓋) = 夢壓鬱鬱獵觸觸觸鏇構廠築鹹簾觸積顧窪範鹽 (衊獵淵鏇願構壓廠繭襯 ) 更多
NCT05158062 (SaINT-ov02, ESMO2026)	临床2期	铂敏感性卵巢癌	26	Pembrolizumab + bevacizumab + platinum-based chemotherapy, followed by pembrolizumab + bevacizumab + olaparib maintenance	醖衊夢構遞簾淵鹽齋鑰(蓋膚壓遞襯繭襯窪餘觸) = 鏇廠鏇積膚獵蓋築繭襯鹽膚獵廠願願構衊窪遞 (壓艱糧範齋鏇觸網艱顧 ) 更多	积极	2026-10-23
NCT04644289 (AGO OVAR 27, ESMO2026)	临床2期	卵巢癌	30	Olaparib 300 mg BID	範範膚壓窪餘廠憲餘夢(夢餘廠淵繭積觸築願膚) = 夢衊淵顧膚餘糧選憲窪構襯鬱獵糧構膚憲鬱鬱 (願夢築網範選衊積窪鹹, 24.6 ~ NR) 更多	积极	2026-10-23