更新于：2024-12-31

Temozolomide

替莫唑胺

更新于：2024-12-31

概要

概要

基本信息

药物类型

小分子化药

别名

3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-1,2,3,5-tetrazine-8-carboxamide、3,4-dihydro-3-methyl-4-oxoimidazo(5,1-d)-as-tetrazine-8-carboxamide、3-methyl-4-oxo-3,4-dihydroimidazo(5,1-d)(1,2,3,5)tetrazine-8-carboxamide

+ [26]

靶点

DNA

作用机制

DNA抑制剂(DNA抑制剂)、DNA烷化剂

治疗领域

肿瘤神经系统疾病皮肤和肌肉骨骼疾病+ [7]

在研适应症

尤文肉瘤脑恶性胶质瘤转移性恶性黑色素瘤+ [71]

非在研适应症

听神经瘤伴有 11q23 异常的急性髓系白血病肾上腺嗜铬细胞瘤+ [100]

原研机构

Merck Sharp & Dohme Corp.

在研机构

National Cancer InstituteSun Pharmaceutical Industries (Europe) BV

Genentech, Inc.

+ [15]

非在研机构

Novartis Pharmaceuticals Corp.

Hexal AGMerck Sharp & Dohme LLC

+ [15]

最高研发阶段批准上市

首次获批日期

欧盟 (1999-01-26),

星形细胞瘤多形性胶质母细胞瘤胶质瘤

最高研发阶段(中国)批准上市

特殊审评加速批准 (美国)、孤儿药 (美国)、孤儿药 (欧盟)、优先审评 (中国)

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结构

分子式C6H6N6O2

InChIKeyBPEGJWRSRHCHSN-UHFFFAOYSA-N

CAS号85622-93-1

关联

1,028

项与替莫唑胺相关的临床试验

NCT06448286 / Not yet recruiting临床3期IIT

PH Weighted Chemical Exchange Saturation Transfer Based Surgical Resections of Glioblastoma

This phase III trial compares pH weighted chemical exchange saturation transfer (CEST) magnetic resonance imaging (MRI)-based surgical resections to standard of care surgical resections for the treatment of patients with glioblastoma. Standard of care therapy for glioblastoma is surgery to remove tumor tissue that enhances on standard MRI imaging, however, it has been shown that significant tumor burden exists in the region around the tumor tissue that does not enhance with standard MRI. MRI is a procedure in which radio waves and a powerful magnet linked to a computer are used to create detailed pictures of areas inside the body. These pictures can show the difference between normal and tumor tissue. CEST MRI is a technique that uses differences in the tissue environment, like protein concentration or intracellular pH, to generate contrast differences. CEST MRI may identify tumor tissue that does not enhance with standard of care MRI. PH weighted CEST MRI based surgical resection may be more effective compared to standard of care surgical resection in treating patients with glioblastoma.

开始日期2025-06-01

申办/合作机构

Jonsson Comprehensive Cancer Center

NCT06649851 / Not yet recruiting临床2期IIT

A Phase 2 Randomized Open-Label Pilot Study of Granulocyte Colony Stimulating Factor (G-CSF) to Preserve Brain Structure and Function Following Standard Chemoradiation in Patients with Newly Diagnosed MGMT-Methylated Glioblastoma

This research study involves the study of granulocyte colony stimulating factor (G-CSF) in patients with MGMT-methylated glioblastoma multiforme (GBM) that are undergoing standard chemoradiation. The study aims to evaluate G-CSF's effects on brain health and cognitive function.
The name of the study drugs involved in this study are:
* G-CSF (also called Filgrastim)
* Temozolomide (TMZ), a standard of care chemotherapy drug

开始日期2025-03-17

申办/合作机构

The General Hospital Corp.

NCT06721689 / Not yet recruiting临床1/2期IIT

A Phase 1/2 Clinical Trial of the Novel Topoisomerase I Inhibitor PEEL-224 As a Single Agent and in Combination with Vincristine and Temozolomide in Children with Refractory, Progressive or Relapsed Solid Tumors

The phase 1 primary objective is to determine the pediatric recommended phase 2 dose (RP2D) of PEEL-224 as a single agent (phase 1A) and in combination with vincristine and temozolomide (phase 1B). The phase 2 primary objective is to estimate the objective response rate (ORR) in children with refractory, progressive and relapsed NBL and rhabdomyosarcoma (RMS) treated with the RP2D of PEEL-224 in combination with vincristine and temozolomide.

开始日期2025-03-01

申办/合作机构

The Children's Hospital of Philadelphia

[+1]

100 项与替莫唑胺相关的临床结果

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100 项与替莫唑胺相关的转化医学

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100 项与替莫唑胺相关的专利（医药）

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10,717

项与替莫唑胺相关的文献（医药）

2025-02-01·CRITICAL REVIEWS IN ONCOLOGY HEMATOLOGY

Neoadjuvant clinical trials in adults with newly diagnosed high-grade glioma: A systematic review

Review

作者: Juarez, Tiffany M ; Sharma, Akanksha ; Kesari, Santosh ; Gill, Jaya M ; Minev, Boris R

BACKGROUND:

High-grade gliomas are devastating cancers that remain incurable with standard surgical resection and radiochemotherapy. Although beneficial against neoplasms, radiation lowers lymphocyte counts, weakens immune activation, and recruits suppressive myeloid cells impairing immune responses. Tumor environments treated with radiation experience long-term immunosuppression, reducing immunotherapy effectiveness and contributing to recurrence. Investigating pre-radiation treatments in newly diagnosed patients could identify active agents, assess immunotherapy impact, and enable multiomic analyses without radiation-induced confounding factors. This literature review was conducted to describe the feasibility, safety, and outcomes of postsurgical, pre-radiation clinical trials for adults with newly diagnosed high-grade glioma.

METHODS:

A systematic review was performed of the English-language literature reporting results of clinical trials for adults with newly diagnosed high-grade glioma administered postsurgical treatment prior to radiation therapy. A search was conducted in PubMed and references cited in research and review articles were also considered.

RESULTS:

From 1991 to 2024, 52 clinical trials were identified: 3 phase I, 38 phase II, 4 phase III, and 7 of unknown phase. Nine trials were randomized, 24 were multicenter trials, 21 investigated temozolomide-containing regimens, and 12 focused on inoperable tumors, involving a total of 2737 patients.

CONCLUSION:

Pre-radiation neoadjuvant studies are feasible and may identify active drugs. This is particularly relevant in the era of personalized medicine with brain-penetrant drugs, targeted therapy, and immuno-oncology advancements. Investigating pre-radiation treatments in newly diagnosed high-grade glioma is a viable approach to rapidly identify active and inactive regimens while the immune system and tumor microenvironment remain intact.

2025-02-01·Bioactive Materials

β-Ketoenamine covalent organic framework nanoplatform combined with immune checkpoint blockade via photodynamic immunotherapy inhibit glioblastoma progression

Article

作者: Shu, Lei ; Zhu, Wenping ; Ye, Qingsong ; Shu, Hongxin ; Sheng, Yilei ; Luo, Min ; Hu, Ping ; Yan, Tengfeng ; Yang, Li ; Xu, Yang ; Liao, Qiuye ; Lei, Chang ; Wang, Li ; Xu, Chun ; Zhu, Xingen ; Wu, Yanze ; Wang, Hongming ; Zhang, Si ; Liu, Junzhe ; Chen, Zhihao

The synergistic approach of combining photodynamic immunotherapy with endogenous clearance of PD-L1 immune checkpoint blockade therapy holds promise for enhancing survival outcomes in glioblastoma (GBM) patients. The observed upregulation of O-GlcNAc glycolysis in tumors may contribute to the stabilization of endogenous PD-L1 protein, facilitating tumor immune evasion. This study presents a pH-adapted excited state intramolecular proton transfer (ESIPT)-isomerized β-ketoamide-based covalent organic framework (COF) nanoplatform (denoted as OT@COF-RVG). Temozolomide (TMZ) and OSMI-4 (O-GlcNAc transferase inhibitor) were integrated into COF cavities, then modified on the surface with polyethylene glycol and the rabies virus peptide RVG-29, showing potential for sensitizing TMZ chemotherapy and initiating photodynamic therapy (PDT). By inhibiting O-GlcNAc and promoting lysosomal degradation of PD-L1, OT@COF-RVG enhanced the effectiveness of immune checkpoint blockade (ICB) therapy. Additionally, treatment with OT@COF-RVG led to a notable elevation in reactive oxygen species (ROS) levels, thereby re-establishing an immunostimulatory state, inducing immunogenic cell death (ICD). In summary, our research unveiled a correlation between O-GlcNAc in GBM and the evasion of immune responses by tumors, while showcasing the potential of OT@COF-RVG in reshaping the immunosuppressive microenvironment of GBM and offering a more effective approach to immunotherapy in clinical settings.

2025-02-01·BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH

Hypoxia enhances IL-8 signaling through inhibiting miR-128-3p expression in glioblastomas

Article

作者: Chen, Ku-Chung ; Chien, Ming-Hsien ; Chen, Peng-Hsu ; Liu, Ann-Jeng ; Ho, Kuo-Hao ; Cheng, Chia-Hsiung ; Hsu, Shao-Yuan

Glioblastoma multiforme (GBM) is an aggressive type of brain tumor known for its hypoxic microenvironment. Understanding the dysregulated mechanisms in hypoxic GBM is crucial for its effective treatment. Through data mining of The Cancer Genome Atlas (TCGA) with hypoxia enrichment scores and in vitro experiments, miR-128-3p was negatively correlated with hypoxia signaling and the epithelial-mesenchymal transition (EMT). Additionally, lower miR-128-3p levels existed in hypoxic GBM, leading to desensitizing temozolomide (TMZ)'s efficacy, a first-line therapeutic drug for GBM. Overexpressing miR-128-3p enhanced both the in vitro and in vivo sensitivity of hypoxic gliomas to TMZ treatment. Mechanistically, HIF-1α suppressed miR-128-3p expression in hypoxic GBM. Through establishing miR-128-3p-mediated transcriptomic profiles and data mining, interleukin (IL)-8 was selected. IL-8 respectively showed positive and negative correlations with hypoxia and miR-128-3p, and was associated with poor TMZ therapeutic results in GBM. Elevated miR-128-3p, which targets both the 3'-untranslated region (UTR) and 5'UTR of IL-8, resulted in suppression of IL-8 expression. Moreover, IL-8 was validated to be involved in HIF-1α/miR-128-3p-regulated TMZ sensitivity and the EMT in hypoxic GBM cells. Collectively, the HIF-1α/miR-128-3p/IL-8 signaling pathway plays a critical role in promoting the progression of hypoxic GBM. Targeting this signaling pathway holds promise as a potential therapeutic strategy.

565

项与替莫唑胺相关的新闻（医药）

2024-12-25

·医药地理

第十批集采拟中选结果价格解析

自12月12日第十批拟中标结果出炉后，关于价格的讨论源源不断，价格这么低正常吗？3分钱的药还能不能吃？基于PDB药物综合数据库药品招标页面相关内容，第十批国家集采拟中选结果共包含62个品种（产品名称）、83个品规（产品名称+剂型规范+规格规范）、210个企业（生产企业）。本文针对该结果进行分析，并按照同一标准和方法统计第二批至第九批的拟中选数据（不含第六批）。口服制剂价格统计不同批次所有口服制剂品规的最小单位价格（即元/片、元/粒等），得到各批次的最高价和最低价。就最值而言，第十批的表现并没有那么突出，既不是最高价中的最低也不是最低价中的最低。如果不计入天士力帝益药业的替莫唑胺胶囊，各批次的最高报价均在百元以内，差异也相对较小。另一方面，几分钱一片的药则是普遍现象，3分钱的对乙酰氨基酚、1分钱的卡托普利、2分钱的二甲双胍、4分钱的硝苯地平、6分钱的美托洛尔等遍布多个批次，第十批3分钱的叶酸和阿司匹林更像是一种延续。至于网传的药效问题，国家医保局曾委托首都医科大学宣武医院分别于2019年和2021年开展了两期真实世界研究，覆盖“4+7”、第二批、第三批不同治疗领域的37个经典一线品种，结果证实“便宜有好药”，仿制药可替代原研药。图1 各批国采口服制剂最小单位价格比较（元）注射制剂价格由于第二批只有1个注射用紫杉醇（白蛋白结合型）、第三批3个注射品种价格偏高，为保持数据可比性，从第四批开始统计所有注射制剂品规的最小单位价格（即元/支、元/瓶等），得到各批次的最高价和最低价。与上述口服制剂的表现不同，第十批确实创造了多个记录：最高价中的最低、最低价中的最低、最窄的价格区间。各批次都曾出现数个百元以上的品种，但第十批只有一个盐酸多柔比星脂质体注射液，且同组内的第一顺位石药欧意仅报价98元，从最初近5000的挂网价到3000多再到不足100，累积降幅超过98%；鉴于石药的白蛋白紫杉醇能从2000多调至747再降为148，国内企业针对高端复杂制剂的能力还是有目共睹的。另外，就最低价而言，除了第五批，其他批次均有多个品种单价低于1元，0.16的氯化钾相较于0.23的地塞米松和氨溴索也没有太大的差距，至于0.22的间苯三酚是否真的亏本，后续市场发展会给出答案。图2 各批国采注射制剂最小单位价格比较（元）价格差距控制针对至少有两家拟中选企业的同一品规，用最高申报价除以最低申报价，计算得到同品规价差倍数，并统计其分布态势，其中第五批的15mg和20mg利伐沙班片因差距过于悬殊（20倍以上）不纳入下方图表。由于第十批强制要求了1.8倍熔断机制，几乎所有品规都位于红线之下，中位数1.44倍，说明大部分企业报价极为接近，零星的离散点则是触发了“小容量注射剂单位可比价小于等于1元”的保底。而在历史集采批次中，第二批作为中选规则出现1.8倍的首个批次，成为了第十批外最接近红线要求的批次。剩余批次的离散程度虽然较大，部分企业更倾向于选择“降幅超过50%”，但红线下方的集中度仍然是最高的，中位数基本稳定在1.48-1.65的区间，平均值则稳定在1.82-2.07，维持了中选后各地区间的价格平衡。图3 各批国采同品规价差倍数分布 END 如需获取更多数据洞察信息或公众号内容合作，请联系医药地理小助手微信号：pharmadl001

带量采购

2024-12-25

·学术经纬

Lancet子刊 | 新联合方案治疗复发性神经母细胞瘤显疗效

撰文 | 陈纹苑责编 | 周叶斌神经母细胞瘤是儿童中最常见的颅外实体肿瘤。约25%的神经母细胞瘤中存在MYCN扩增，这通常预示着较差的预后。高危神经母细胞瘤患者即使接受了强化的多模式治疗仍有超过一半的患者会在诊断后两年内复发。此外，10-20%的患者对一线化疗显示耐药性。对于复发性高危神经母细胞瘤患者，其4年无进展生存率和总生存率仅分别为6%和20%，而中位无进展生存期仅为6.4个月，这凸显了高危神经母细胞瘤作为儿童癌症中最为严峻疾病之一的挑战性。尽管预后挑战巨大，但研究表明，伊立替康（Irinotecan）和替莫唑胺（temozolomide）在复发性和难治性神经母细胞瘤中显示出疗效；此外，mTOR信号通路在神经母细胞瘤中具有重要作用。临床前研究中，mTOR抑制剂雷帕霉素（rapamycin）与酪氨酸激酶（tyrosine kinase）抑制剂协同作用显著，能诱导放射增敏和化疗增敏。这种效果在MYCN扩增的神经母细胞瘤中尤其突出，为后续临床研究奠定了基础。近日，由 Dr Selim Corbacioglu 团队发表于 Lancet Oncology 题为 Irinotecan and temozolomide in combination with dasatinib and rapamycin versus irinotecan and temozolomide for patients with relapsed or refractory neuroblastoma (RIST-rNB-2011): a multicentre, open-label, randomised, controlled, phase 2 trial 的文章，首次探索了代谢节律性、途径导向的四药联合疗法的疗效，这项二期临床试验RIST-rNB-2011显示，雷帕霉素-达沙替尼联合伊立替康-替莫唑胺可显著延长MYCN扩增型复发性神经母细胞瘤患者的无进展生存期（PFS）和总体生存期（OS），同时具有良好的耐受性。这一发现也为RIST方案成为潜在的一线治疗方案提供了可能。 RIST-rNB-2011是一项在德国和奥地利的40家儿童肿瘤中心进行的II期临床试验。从2013年到2020年招募的对象包括1至25岁的儿童、青少年和年轻成人（Lansky或Karnofsky体能评分至少50%）。这些患者均为高危（国际神经母细胞瘤分期系统[INSS] IV期病灶或所有MYCN扩增分期）复发（定义为治疗后出现复发，包括多次复发，且不限制既往治疗）神经母细胞瘤患者，已接受强化的多模式高危治疗，或为耐药性神经母细胞瘤患者（初始治疗期间病情进展）。本试验一共招募了129名患者；他们被随机1:1分配至RIST组或伊立替康-替莫唑胺（对照组）并确保各组中MYCN扩增患者均匀分布。（详情见图一）图一：试验流程图 RIST组治疗方案由雷帕霉素-达沙替尼疗程和伊立替康-替莫唑胺疗程交替组成，总疗程为20周。雷帕霉素-达沙替尼疗程中，患者第1天接受口服雷帕霉素的负荷剂量（3 mg/m²），随后在第2至第4天调整为维持剂量（1 mg/m²），同时每日口服达沙替尼（2 mg/kg，最大剂量140 mg/天），持续4天后停药3天。在第5天通过血清检测监测雷帕霉素浓度，并调整后续疗程的剂量至3–10 ng/mL范围，以确保治疗的稳定性和有效性。伊立替康-替莫唑胺疗程包括每日口服替莫唑胺（150 mg/m²）和静脉注射伊立替康（50 mg/m²），连续5天后停药2天，以完成一个疗程。试验设计分为两个阶段：第一阶段（8周）：包括4个周期，每个周期由1个雷帕霉素-达沙替尼疗程和1个伊立替康-替莫唑胺疗程组成。第二阶段（12周）：包括4个周期，但每周期调整为2个雷帕霉素-达沙替尼疗程和1个伊立替康-替莫唑胺疗程，以增加靶向治疗的比例。第二阶段的设计旨在减少化疗相关毒性，例如血液系统损伤，从而避免治疗延迟，并为患者提供更充足的血液系统恢复时间。同时，通过持续使用靶向药物维持对癌细胞的抑制作用。这种代谢节律性方案确保了治疗的有效性，同时最大限度地减少了不良反应的发生。对照组接受标准的8个伊立替康-替莫唑胺疗程。本次试验主要终点是无进展生存期(PFS)，次要终点包括总体生存期（OS)。本次试验结果如下：主要终点：无进展生存期（PFS）在意向治疗人群(n=124)中： RIST组（n=49）的中位无进展生存期为11个月（95% CI 7–17），对照组（n=54) 为5个月（2–8）（HR 0.62，p=0.019）。（见图二A） MYCN扩增患者中，RIST组的中位PFS显著长于对照组（6个月 vs 2个月，p=0.012）。非MYCN扩增患者中，RIST组与对照组差异不显著（14个月 vs 8个月，p=0.49）。次要终点：总体生存期（OS） RIST组的中位总体生存期为20个月（95% CI 13–30），对照组为16个月（10–22），但未达到统计学显著性（p=0.073）。巩固治疗中的表现基于医生决策的单倍体造血干细胞移植中，MYCN扩增患者在RIST组的生存率更高（83% vs 0%）。这可能归因于RIST治疗帮助患者实现了**最小残留病灶（MRD）**状态，从而允许更持久的细胞巩固治疗。不良事件 RIST组的毒性反应与对照组相似，未发现显著差异。图二：无进展生存期（PFS）和总体生存期（OS) 因此，RIST治疗显著改善了无进展生存期（PFS），并使复发或难治性神经母细胞瘤患者的总体生存期（OS）明显延长（虽然未达到统计学显著性）。并且RIST的协同作用在MYCN扩增的肿瘤和细胞系中尤为显著。本试验也探究为什么MYCN扩增患者在接受RIST治疗和单倍体造血干细胞移植后生存率更高；这可能是因为这些患者达到了最小残留病灶（MRD）状态，从而能够进行持久的细胞巩固治疗。因此，RIST治疗能够在MYCN扩增的复发或难治性神经母细胞瘤患者中诱导缓解，并实现持续的无进展生存。因此未来试验需要进一步确定最适合的巩固治疗方案。所以RIST试验的结果为MYCN扩增型神经母细胞瘤患者在一线治疗中采用类似RIST的治疗方案提供了新的讨论方向。即使本试验仍然存在局限性（招募周期较长，符合方案人群样本少，观察到的毒性反应导致方案违背几乎完全于与伊立替康-替莫唑胺)，但是RIST试验首次表明，在MYCN扩增型复发或难治性神经母细胞瘤患者中，雷帕霉素-达沙替尼联合伊立替康-替莫唑胺能够改善长期的无进展生存期（PFS）和总体生存期（OS），证明了MYCN扩增是一个具有临床相关性的分子靶点。本研究中使用的药物普遍可及，多数为口服液制剂，且适用于门诊治疗，同时具有可接受的不良事件特征，这表明RIST方案可能成为最脆弱的神经母细胞瘤患者的一种潜在治疗选择。撰文责编制作排版 | 车洁校对 | uu 延伸阅读依维莫司在复发或进展性儿童低级别胶质瘤中呈现疗效！ *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） Background: Neuroblastoma is the most common extracranial solid tumour in children. Relapsed or refractory neuroblastoma is associated with a poor outcome. We assessed the combination of irinotecan-temozolomide and dasatinib-rapamycin (RIST) in patients with relapsed or refractory neuroblastoma. Methods: The multicentre, open-label, randomised, controlled, phase 2, RIST-rNB-2011 trial recruited from 40 paediatric oncology centres in Germany and Austria. Patients aged 1-25 years with high-risk relapsed (defined as recurrence of all stage IV and MYCN amplification stages, after response to treatment) or refractory (progressive disease during primary treatment) neuroblastoma, with Lansky and Karnofsky performance status at least 50%, were assigned (1:1) to RIST (RIST group) or irinotecan-temozolomide (control group) by block randomisation, stratified by MYCN status. We compared RIST (oral rapamycin [loading 3 mg/m2 on day 1, maintenance 1 mg/m2 on days 2-4] and oral dasatinib [2 mg/kg per day] for 4 days with 3 days off, followed by intravenous irinotecan [50 mg/m2 per day] and oral temozolomide [150 mg/m2 per day] for 5 days with 2 days off; one course each of rapamycin-dasatinib and irinotecan-temozolomide for four cycles over 8 weeks, then two courses of rapamycin-dasatinib followed by one course of irinotecan-temozolomide for 12 weeks) with irinotecan-temozolomide alone (with identical dosing as experimental group). The primary endpoint of progression-free survival was analysed in all eligible patients who received at least one course of therapy. The safety population consisted of all patients who received at least one course of therapy and had at least one post-baseline safety assessment. This trial is registered at ClinicalTrials.gov, NCT01467986, and is closed to accrual. Findings: Between Aug 26, 2013, and Sept 21, 2020, 129 patients were randomly assigned to the RIST group (n=63) or control group (n=66). Median age was 5·4 years (IQR 3·7-8·1). 124 patients (78 [63%] male and 46 [37%] female) were included in the efficacy analysis. At a median follow-up of 72 months (IQR 31-88), the median progression-free survival was 11 months (95% CI 7-17) in the RIST group and 5 months (2-8) in the control group (hazard ratio 0·62, one-sided 90% CI 0·81; p=0·019). Median progression-free survival in patients with amplified MYCN (n=48) was 6 months (95% CI 4-24) in the RIST group versus 2 months (2-5) in the control group (HR 0·45 [95% CI 0·24-0·84], p=0·012); median progression-free survival in patients without amplified MYCN (n=76) was 14 months (95% CI 9-7) in the RIST group versus 8 months (4-15) in the control group (HR 0·84 [95% CI 0·51-1·38], p=0·49). The most common grade 3 or worse adverse events were neutropenia (54 [81%] of 67 patients given RIST vs 49 [82%] of 60 patients given control), thrombocytopenia (45 [67%] vs 41 [68%]), and anaemia (39 [58%] vs 38 [63%]). Nine serious treatment-related adverse events were reported (five patients given control and four patients given RIST). There were no treatment-related deaths in the control group and one in the RIST group (multiorgan failure). Interpretation: RIST-rNB-2011 demonstrated that targeting of MYCN-amplified relapsed or refractory neuroblastoma with a pathway-directed metronomic combination of a multkinase inhibitor and an mTOR inhibitor can improve progression-free survival and overall survival. This exclusive efficacy in MYCN-amplified, relapsed neuroblastoma warrants further investigation in the first-line setting. Funding: Deutsche Krebshilfe. DOI: 10.1016/S1470-2045(24)00202-X 👇点击此处，直达原文

临床2期临床结果申请上市临床终止寡核苷酸

2024-12-20

·奇点网

癌细胞也过上日出日落的规矩日子了？想多了

*仅供医学专业人士阅读参考周期和节律的力量，总显得神秘且博大。前两天奇点糕才提到，月经周期可能是操控乳腺癌化疗效果的幕后力量，没想到人体内的另一种重要节律——生物钟，也很快就“不甘寂寞”，要出来刷刷存在感啦，而且受它摆布的，竟然是致命的胶质母细胞瘤（GBM）？！近日，美国圣路易斯华盛顿大学（WUSTL）研究团队在Cancer Cell期刊发表的最新研究成果显示，GBM的生长会在糖皮质激素调控下与人体昼夜节律同步，对此起主要调控作用的是核心生物钟基因Bmal1和Cry，而通过阻断糖皮质激素受体（GR）信号来打破生物钟的调控作用，即可显著抑制GBM生长，有效延缓疾病进展[1]。一图总结论文核心内容对脑部肿瘤稍有了解的读者们应该都知道，GBM在常见脑瘤中向来以治疗难度大、患者预后极差著称，手术切除后基本必复发、且对大多数化疗不敏感，也是GBM两大臭名昭著的特征。但开展本次研究的WUSTL团队此前就发现，在早上接受GBM常用化疗药替莫唑胺治疗的患者，中位总生存期（OS）竟可能比晚上接受化疗的患者至多长6个月[2]。6个月的中位OS差异，在GBM治疗领域说“颠覆性”可能还有点夸张，但已经是各种创新治疗手段望尘莫及的了，当然要开展研究明确原因。WUSTL团队今年早些时候发表的一项研究就显示，GBM中常能见到的MGMT基因（多为启动子部位甲基化），其表达水平就存在昼夜节律变化[3]，可用于指导替莫唑胺治疗时机，但结论能否外推到全部GBM呢？而能让研究者们把上面这些线索和糖皮质激素串到一起的，则是既往研究和日常实验中，GBM本身的节律变化并不容易被打乱，这与许多常见癌症不同，于是研究者们推测，体内可能有某种神经肽或激素调控了GBM，使它们更容易与昼夜节律同步，也更不易被干扰；而人体大脑内负责调控昼夜节律的视交叉上核（SCN），恰好也负责调控糖皮质激素分泌。猜想的证据链看起来很完整对吧？那就验证一下看看。研究者们首先在体外实验中证实，GBM细胞的Bmal1和Per2等生物钟基因表达有内在昼夜节律，而在Per2表达的低谷期使用地塞米松（DEX）处理，会使GBM的生长加速3倍，反过来在Per2表达的高峰期用DEX处理，抑制效果也会是3倍，且这种调控依赖于GBM细胞表达GR。在生物钟基因表达的高峰或低谷期使用DEX处理，对GBM的影响截然相反随后在小鼠体内的实验结论同样显示，GBM内生物钟基因表达保留了内在昼夜节律，而在早上（对应GBM细胞Per2表达低谷期）使用DEX处理，促GBM生长的效果也最明显。研究者们提出的模型认为，宿主体内夜间高表达的生物钟基因Per1/2和Cry，会有效抑制GR信号通路，使GBM难以加速增殖；但到了早上Bmal1基因被激活，情况就逆转过来了。而与外源性的DEX一样，人或小鼠体内的内源性糖皮质激素信号（皮质醇/皮质酮）也会对GBM生长起到调控作用，且敲低GR可显著延缓GBM生长；癌症基因组图谱计划（TCGA）的数据也显示，GBM患者GR编码基因NR3C1表达水平，与生存预后显著相关。值得注意的是，内源性糖皮质激素对GBM生长的调控作用是要“日常性”存在的：研究者们通过敲除小鼠血管活性肠肽（VIP）基因、导致小鼠睡眠-觉醒规律紊乱证实，伴随着日常睡眠-觉醒发生的糖皮质激素激增（Surge）对维持GBM生长不可或缺；逆转光照周期实验还证实，糖皮质激素的日常调控，也确实会使GBM自身的昼夜节律与宿主保持同步。打乱宿主的昼夜节律可有效抑制GBM生长在论文长长的讨论部分里，研究者们提到了本次研究揭示的各种潜在可能性，例如临床对GBM患者使用糖皮质激素（通常目的为减轻治疗导致的脑水肿）的时机或需优化，以在促癌/抑癌方面扬长避短、找对时间让替莫唑胺实现“节律化疗”、靶向GR通路作为抑制GBM的手段等等等等，奇点糕太能理解这种心态了，GBM啊，难倒太多人，夺走太多命了，每一点进步都难能可贵，当然要想办法去探索各种可能性啦。参考文献：[1]Gonzalez-Aponte M F, Damato A R, Simon T, et al. Daily glucocorticoids promote glioblastoma growth and circadian synchrony to the host[J]. Cancer Cell, 2024.[2]Damato A R, Luo J, Katumba R G N, et al. Temozolomide chronotherapy in patients with glioblastoma: a retrospective single-institute study[J]. Neuro-Oncology Advances, 2021, 3(1): vdab041.[3]Gonzalez-Aponte M F, Damato A R, Trebucq L L, et al. Circadian regulation of MGMT expression and promoter methylation underlies daily rhythms in TMZ sensitivity in glioblastoma[J]. Journal of Neuro-Oncology, 2024, 166(3): 419-430.本文作者丨谭硕

临床结果临床2期

100 项与替莫唑胺相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D06067	替莫唑胺	L01AX03	DB00853

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
尤文肉瘤	日本	Ohara Pharmaceutical Co., Ltd.	2019-02-21
尤文肉瘤	日本	MSD KK	2019-02-21
脑恶性胶质瘤	欧盟	Teva Pharmaceuticals Europe BV	2010-01-28
脑恶性胶质瘤	冰岛	Teva Pharmaceuticals Europe BV	2010-01-28
脑恶性胶质瘤	列支敦士登	Teva Pharmaceuticals Europe BV	2010-01-28
脑恶性胶质瘤	挪威	Teva Pharmaceuticals Europe BV	2010-01-28
转移性恶性黑色素瘤	澳大利亚	Merck Sharp & Dohme (Australia) Pty Ltd.	2009-11-13
胶质母细胞瘤	中国	江苏天士力帝益药业有限公司	2004-04-30
星形细胞瘤	欧盟	Merck Sharp & Dohme BV	1999-01-26
星形细胞瘤	冰岛	Merck Sharp & Dohme BV	1999-01-26
星形细胞瘤	列支敦士登	Merck Sharp & Dohme BV	1999-01-26
星形细胞瘤	挪威	Merck Sharp & Dohme BV	1999-01-26
多形性胶质母细胞瘤	欧盟	Merck Sharp & Dohme BV	1999-01-26
多形性胶质母细胞瘤	冰岛	Merck Sharp & Dohme BV	1999-01-26
多形性胶质母细胞瘤	列支敦士登	Merck Sharp & Dohme BV	1999-01-26
多形性胶质母细胞瘤	挪威	Merck Sharp & Dohme BV	1999-01-26
胶质瘤	欧盟	Merck Sharp & Dohme BV	1999-01-26
胶质瘤	冰岛	Merck Sharp & Dohme BV	1999-01-26
胶质瘤	列支敦士登	Merck Sharp & Dohme BV	1999-01-26
胶质瘤	挪威	Merck Sharp & Dohme BV	1999-01-26

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
神经母细胞瘤	申请上市	欧盟	ORPHELIA Pharma SAS	2024-11-14
子宫平滑肌肉瘤	临床3期	美国	National Cancer Institute	2022-03-30
脑干胶质瘤	临床3期	美国	National Cancer Institute	2011-01-26
脑干胶质瘤	临床3期	加拿大	National Cancer Institute	2011-01-26
成人脑星形细胞瘤	临床3期	美国	National Cancer Institute	2011-01-26
成人脑星形细胞瘤	临床3期	加拿大	National Cancer Institute	2011-01-26
高级别胶质瘤	临床3期	美国	National Cancer Institute	2011-01-26
高级别胶质瘤	临床3期	加拿大	National Cancer Institute	2011-01-26
小儿小脑星形细胞瘤	临床3期	美国	National Cancer Institute	2011-01-26
小儿小脑星形细胞瘤	临床3期	加拿大	National Cancer Institute	2011-01-26

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适应症

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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


NCT02152982 (Alliance for Clinical Trials in Oncology, Pubmed \| JAMA Oncol)	临床3期	多形性胶质母细胞瘤 \| 神经胶质肉瘤辅助 MGMT promoter hypermethylation	447	Veliparib + Temozolomide	鹽構壓蓋襯窪鏇夢積窪(繭築窪鑰範膚構獵簾遞) = The experimental combination was well tolerated with an acceptable elevation in grade 3 or 4 hematologic toxic effects 構鏇鬱繭願艱壓淵壓衊 (壓糧糧獵獵艱鬱願膚鏇 ) 更多	不佳	2024-12-01
				Placebo + Temozolomide
RADT-09 (SNO2024)	N/A	IDH wild-type \| TERT promoter mutation	21	Chemoradiotherapy with Temozolomide	積鑰製夢衊積蓋襯積鏇(餘襯窪壓憲艱鑰獵襯獵) = 繭膚糧願鬱積窪壓願繭夢憲觸鏇鹹廠顧蓋窪製 (構築鹹築齋窪壓築衊廠 ) 更多	积极	2024-11-11
				Radiotherapy alone	積鑰製夢衊積蓋襯積鏇(餘襯窪壓憲艱鑰獵襯獵) = 範淵憲積衊淵鹹選齋鹽夢憲觸鏇鹹廠顧蓋窪製 (構築鹹築齋窪壓築衊廠 ) 更多
phase II clinical study (SNO2024)	临床2期	胶质母细胞瘤维持 MGMT status	69	TTFields therapy concomitant with RT/TMZ	網膚獵醖齋淵襯鑰製鹽(淵範鏇窪壓顧醖構糧窪) = 顧觸醖窪製鏇憲簾餘窪鏇鹽顧顧廠廠鹹壓憲蓋 (網壓蓋範網繭遞構艱鑰 ) 更多	积极	2024-11-11
				RT/TMZ alone	網膚獵醖齋淵襯鑰製鹽(淵範鏇窪壓顧醖構糧窪) = 夢鏇遞選鏇獵廠醖觸選鏇鹽顧顧廠廠鹹壓憲蓋 (網壓蓋範網繭遞構艱鑰 ) 更多
QLTI-22 (SNO2024)	N/A	胶质瘤	13	Patients who received Temozolomide chemotherapy	淵構觸壓鏇窪蓋鹽鏇鬱(醖積窪願簾醖築積齋憲) = 鏇醖齋淵艱壓鏇選襯窪糧壓衊餘壓製鑰鑰鏇窪 (壓襯鬱壓廠糧遞顧餘網 ) 更多	-	2024-11-11
SNO2024	N/A	胶质母细胞瘤一线	-	Temozolomide Chemoradiation	範構醖繭廠夢淵鏇憲膚(艱簾繭蓋鹹遞膚鑰夢獵) = 膚積餘鏇範構網窪夢鬱顧醖廠積糧觸襯顧網顧 (顧範鏇蓋壓鹽夢範繭襯 )	积极	2024-11-11
				Placebo	範構醖繭廠夢淵鏇憲膚(艱簾繭蓋鹹遞膚鑰夢獵) = 鏇餘構簾鬱齋積鏇簾廠顧醖廠積糧觸襯顧網顧 (顧範鏇蓋壓鹽夢範繭襯 )
INNV-27 (SNO2024)	N/A	垂体肿瘤 MGMT methylation status	8	Temozolomide	衊獵築鹹膚製繭遞鏇製(廠鏇壓遞構繭衊艱廠壓) = 觸窪遞繭遞廠淵顧鬱鹽憲餘鑰壓繭糧築鑰鬱積 (網鹹觸襯築繭簾構齋齋 )	积极	2024-11-11
CNSC-35 (SNO2024)	N/A	弥漫内生性脑桥神经胶质瘤辅助	28	Adjuvant Temozolomide	膚願鑰製餘網積遞範蓋(獵鬱窪醖願膚壓淵餘鏇) = 鹽艱糧襯餘壓糧簾蓋簾築糧醖齋網襯簾淵積積 (淵膚廠積鹹艱範襯窪醖, 5 ~ 10.7)	积极	2024-11-11
				No Adjuvant Temozolomide	膚願鑰製餘網積遞範蓋(獵鬱窪醖願膚壓淵餘鏇) = 網獵遞蓋艱顧餘鑰遞觸築糧醖齋網襯簾淵積積 (淵膚廠積鹹艱範襯窪醖, 2.3 ~ NA)
INB-200 (SNO2024)	临床1期	多形性胶质母细胞瘤维持 IDH wild type \| mutant tumors \| MGMT unmethylated	23	Temozolomide (Cohort 1 (1 x 10^7 DRI cells/dose))	餘觸鬱網觸餘範蓋窪蓋(膚觸製簾淵窪簾網鏇製) = The most common adverse events were decreased WBC/platelet count 選鏇襯積廠衊淵繭顧範 (獵醖顧獵齋壓觸蓋網選 )	积极	2024-11-11
				Temozolomide (Cohort 2 (1 x 10^7 DRI cells/dose))
P18.08.A (EANO2024)	N/A	胶质母细胞瘤 MGMT-methylated \| IDH-wildtype	17	CCNU/TMZ	製膚願衊願艱範廠鬱構(鹽選築廠艱壓鏇顧窪築) = 廠構襯願鏇範鹹齋顧壓獵衊獵窪醖蓋憲窪鑰製 (壓齋獵簾壓廠窪鑰製製, 17.6 ~ not reached) 更多	积极	2024-10-17
P26.12.A (EANO2024)	N/A	胶质母细胞瘤	8	Itraconazole	構餘窪鏇鏇夢鏇淵範獵(夢襯鏇顧遞襯膚膚夢簾) = 糧壓網蓋廠餘蓋淵範窪製遞鏇遞顧顧壓衊範廠 (襯鹽繭淵齋膚蓋餘憲衊 ) 更多	积极	2024-10-17
				Pyrimethamine	構餘窪鏇鏇夢鏇淵範獵(夢襯鏇顧遞襯膚膚夢簾) = 鹽廠憲餘夢獵繭願選壓製遞鏇遞顧顧壓衊範廠 (襯鹽繭淵齋膚蓋餘憲衊 )