Supported by the pre-clinical data (summarized in Research Strategy), the investigators propose that Fimepinostat is an ideal candidate drug in the treatment and intervention of patients with Cushing Disease. The investigators propose a pilot, short-term (4 weeks) phase II single-center study to demonstrate the safety and efficacy of Fimepinostat in the treatment of patients with de novo, persistent, and/or recurrent CD recruited at the University of California, Los Angeles. The trial will have a 2-arm design and will simultaneously examine two different doses of Fimepinostat. The study will allow the investigators to determine the efficacy and safety of these doses in the treatment of CD and guide dose selection for subsequent, larger studies. Funding Source - FDA OOPD.

开始日期2025-01-16

申办/合作机构

University of California, Los Angeles

NCT03893487

/ Active, not recruiting早期临床1期IIT

A Target Validation Study of Fimepinostat in Children and Young Adults With Newly Diagnosed Diffuse Intrinsic Pontine Glioma (DIPG), Recurrent Medulloblastoma, or Recurrent High-Grade Glioma (HGG)

This trial studies how well fimepinostat works in treating patients with newly diagnosed diffuse intrinsic pontine glioma, or medulloblastoma, or high-grade glioma that have come back. Fimepinostat may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

开始日期2019-08-07

申办/合作机构

The University of California, San Francisco

[+1]

NCT03002623

/ Terminated临床2期IIT

A Phase II Trial of CUDC-907 in Patients With Metastatic and Locally Advanced Thyroid Cancer

Background:
The thyroid is a gland at the base of the throat. Thyroid cancer is a disease that people get when abnormal cells begin to grow in this gland. Researchers believe a new drug called CUDC-907 may be able to help people with thyroid cancer that has spread or has gotten worse.
Objective:
To see if CUDC-907 will shrink tumors in people with advanced thyroid cancer.
Eligibility:
People at least 18 years old who have been diagnosed with locally advanced and metastatic thyroid cancer.
Design:
Participants will be screened with:
Medical history
Physical exam
Blood and urine tests
Electrocardiogram (ECG) heart test.
Review of their symptoms and how they perform normal activities
A scan will be performed. Some will have a computed tomographic scan (CT) that takes pictures of the body using a small amount of radiation. Some will have magnetic resonance imaging (MRI) that uses a magnetic field to take pictures.
Bone scan (some participants)
Fludeoxyglucose (FDG) positron emission tomography (PET) scan to produce a tumor image.
A sample of their tumor from a previous surgery. They may have a biopsy of their tumor if a tumor sample is not available from a previous surgery.
Participants will be given CUDC-907 in tablet form. They will take it by mouth once a day for 5 days, then take 2 days off, each week.
While taking the study drug, participants will have study visits that repeat the screening tests.
After they stop treatment, participants will have 3 follow-up visits over a year. They will repeat some tests. Then participants will be contacted by phone or e-mail every 6 months....

开始日期2016-12-22

申办/合作机构

National Cancer Institute

100 项与 Fimepinostat 相关的临床结果

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100 项与 Fimepinostat 相关的转化医学

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100 项与 Fimepinostat 相关的专利（医药）

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121

项与 Fimepinostat 相关的文献（医药）

2025-06-01·Cancer research communications

Histone Deacetylase Inhibitors Target DNA Replication Regulators and Replication Stress in Ewing Sarcoma Cells

Article

作者: Quelle, Dawn E. ; Gedminas, Jenna M. ; Dodd, Rebecca D. ; Thomas, Mary V. ; Koppenhafer, Stacia L. ; Geary, Elizabeth L. ; Gordon, David J. ; Zimmerman, Jessica A.O. ; Croushore, Emma E.

Abstract:

Histone deacetylases (HDAC) regulate diverse pathways in cancer cells. Previously, we identified that Ewing sarcoma tumors, which are caused by a translocation between the EWSR1 and FLI1 genes (EWS::FLI1), are sensitive to drugs that target DNA replication, including the RRM1 and RRM2 subunits of ribonucleotide reductase, and the ATR–checkpoint kinase 1 (CHK1)–WEE1 signaling pathway. In this study, we identified that multiple HDAC inhibitors, including fimepinostat, romidepsin, and panobinostat, downregulate the levels of the RRM1, RRM2, CHK1, and WEE1 proteins in Ewing sarcoma cells and impair DNA replication. Moreover, transcriptome analyses identified that HDAC inhibitors downregulate the expression of multiple components of the prereplication complex, including the minichromosome maintenance complex 2–7 (MCM2–7) proteins and CDT1, that are essential for genomic DNA replication. Additionally, proteomic studies identified that HDAC inhibitors also downregulate the level of the BRD4 protein, a BET bromodomain protein that regulates both the transcriptional program of the EWS::FLI1 oncoprotein and DNA replication. Overall, these results provide novel insight into the molecular mechanisms by which HDAC inhibitors target cancer cells, regulate DNA replication, and inhibit the cellular response to DNA replication stress.

Significance::

In this work, we identify that HDAC inhibitors broadly disrupt DNA replication and the response to replication stress in Ewing sarcoma cells by downregulating RRM1, RRM2, CHK1, and WEE1. Notably, HDAC inhibitors also reduce MCM2–7 proteins, which are essential for prereplication complex helicase function in replication initiation and elongation, and CDT1, which loads MCM2–7 onto DNA.

2025-04-01·BIOORGANIC & MEDICINAL CHEMISTRY

Thienopyrimidine: A promising scaffold in the development of kinase inhibitors with anticancer activities

Review

作者: Song, Jian ; Wang, Zi-Yue ; Zhang, Sai-Yang ; Liu, Yun-He ; Liu, Xuan-Han ; Niu, Jin-Bo ; Du, Yi-Fei ; Jin, Cheng-Yun

Protein kinases represent a highly promising drug target, with over 80 drugs that target about two dozen different protein kinases have been approved by the US FDA, particularly in cancer treatment. Over the past decades, the unique structural characteristics of the thienopyrimidine ring system provide an adaptive platform for designing potent anticancer agents, especially various kinase inhibitors, which has attracted widespread attention. Some of these thienopyrimidines as anticancer kinase inhibitors have already been marketed or are currently undergoing clinical/preclinical studies for the treatment of cancers, such as Olmutinib, Pictilisib, SNS-314, PF-03758309, and Fimepinostat, highlighting the substantial advantages of the thienopyrimidine scaffold in the discovery of anticancer agents. This article reviews the discovery, activity, and structure-activity relationships of antitumor kinase inhibitors based on the thienopyrimidine scaffold, and partially discusses the binding modes between thienopyrimidine derivatives and their kinase targets. By elucidating the application of thienopyrimidine derivatives as anticancer kinase inhibitors, this review aims to provide new perspectives for the development of more effective and novel kinase inhibitors.

2025-03-07·NEURO-ONCOLOGY

TRIM21-mediated ubiquitination and phosphorylation of ERK1/2 promotes cell proliferation and drug resistance in pituitary adenomas

Article

作者: Li, Chuanbao ; Han, Tianyi ; Lin, Shaojian ; Wu, Zhe Bao ; Xue, Li ; Huang, Ning ; Tang, Hao ; Wang, Xiaobin ; Dai, Yuting ; Liu, Yanting ; Liu, Fang ; Zhang, Tao

Abstract:

Background:

Pituitary adenomas (PAs) are common intracranial tumors and the TRIM family plays a crucial role in cell proliferation and therapeutic resistance of tumors. However, the role of the TRIM family in PAs is not well recognized.

Methods:

CRISPR screening explored the role of the TRIM family in cell proliferation and drug resistance in PAs. In vitro and in vivo experiments were performed to evaluate the effects of Tripartite Motif Containing 21 (TRIM21). RNA-sequencing, mass spectrometry, immunoprecipitation, and ubiquitination experiments were performed to explore the molecular mechanism. NanoBiT assays were used to screen the drugs reducing TRIM21 expression.

Results:

CRISPR-Cas9 screens identified that TRIM21 facilitated cell proliferation and drug resistance in PAs. Mechanistically, TRIM21 interacted with ERK1/2 through PRY-SPRY domain, leading to ERK1/2 K27-linked ubiquitination. The ERK1/2 ubiquitination promotes the interaction between ERK1/2 and MEK1/2, thereby facilitating the phosphorylation of ERK1/2. However, an excess presence of TRIM21 suppressed the phosphorylation of ERK1/2 and cell proliferation via activating ERK1/2 negative feedback pathways. Importantly, TRIM21 was upregulated in dopamine-resistant prolactinomas and cabergoline-resistant MMQ cells. Furthermore, drug screening identified that Fimepinostat and Quisinostat, can reduce the protein levels of TRIM21, inhibit tumor progression, and increase drug sensitivity.

Conclusions:

TRIM21 may represent a therapeutic target for tumors, and inhibiting TRIM21 could be a potential strategy for tumor treatment.

项与 Fimepinostat 相关的新闻（医药）

2025-07-07

·同写意

药监局四连批启示：抛弃“平替”角色的“全球首创”中国新药

同写意年度巨献！！7月25-26日，邀您相聚金鸡湖畔，与5000人一起为中国医药创新“同写意”！TONACEA01从ifupinostat看中国创新药崛起的全球化坐标2025年7月初，中国国家药监局一日内连批四款由本土药企开发的新药，涵盖两款小分子两款抗体药物。这在惯常的新药审批节奏中并不罕见，但本次批准的品种却不容小觑。其中既包括全球首个机制类新药ifupinostat，也有对标国际重磅药的乳腺癌CDK4/6抑制剂tibremciclib，还有突破铂类耐药瓶颈的抗VEGF抗体，以及填补痛风治疗空白的IL-1β生物制剂。在这些产品背后，我们看到的已不再是“仿制替代”的逻辑，而是机制差异化、适应症先发、全球竞品对接的新路径。它们代表着中国本土生物科技在机制创新、临床设计、患者定位与国际竞争中的多重发力，也让从中国诞生的全球首创药不再只是个例。TONACEA02Ifupinostat：双靶点的中国式解法，打破“靶点孤岛”• Ifupinostat获批历程Ifupinostat（BEBT-908）是由必贝特医药（BeBetter Med）研发的小分子抗肿瘤药物，作用于HDAC（组蛋白脱乙酰酶）和PI3K（磷脂酰肌醇-3-激酶）两个关键通路。在治疗弥漫大B细胞淋巴瘤（DLBCL）中，它成为全球首款获批的HDAC/PI3K双重抑制剂药物。国际上，美国Curis公司曾开发结构相似的fimepinostat，并于2018年获得FDA快速通道认定，但Curis最终将主要精力集中在了另一项B细胞淋巴瘤资产IRAK4抑制剂emavusertib项目上而终止了fimepinostat的开发。ifupinostat则在中国完成了关键性2b期试验，在经过两线以上治疗失败的DLBCL患者中获得33.8%的ORR；如果剔除疫情造成的脱落与偏差，ORR可达53.6%。更值得关注的是，在接受过CAR-T或双抗治疗仍无效的患者中，其ORR达67%，展现出在免疫治疗失败患者群体中的差异化价值。• Ifupinostat获批意义相比动辄百万元一疗程的CAR-T治疗，ifupinostat作为口服小分子药物，更具性价比优势，也更容易在医保体系中获得广泛应用。目前该药已进入三期验证性临床，联合利妥昔单抗（rituximab）用于二线DLBCL治疗，早期数据显示ORR达76.2%，在今年ASCO会议上获得关注。Ifupinostat 的获批意义并不仅在于“首创”这两个字，而在于它对靶点协同策略的首次商业化验证。HDAC 和 PI3K 作为两个独立存在于多种癌症进程中的关键酶靶点，曾长期被认为不易联用：前者影响表观遗传调控，后者主导细胞增殖与存活信号通路，双抑制可能导致毒性增强，亦可能信号互扰。而 ifupinostat 的成功，意味着通过合理分子设计和平衡抑制谱，这一“协同-非冗余”的靶点组合被首次转化为可行的临床药物。对全球血液瘤药物开发而言，这一里程碑事件无异于打开了非免疫类新机制的另一个入口。在 CAR-T 和双抗主导的当前格局下，小分子产品的空间逐渐被压缩，但 ifupinostat 提供了一个清晰的例证：在免疫疗法失败后的患者中，机制迥异的小分子依然能带来真实的治疗获益。这不仅为 PI3K 研发领域注入新活力，也可能推动其他多靶点协同策略如HDAC/BTK、PI3K/BRD4等组合加速向临床过渡。而从患者角度看，它更意味着一种可负担、易使用、作用机制不同的选择，尤其是对于那些曾被告知“CAR-T失败后别无选择”的患者而言，ifupinostat给出了一条全新的生路。TONACEA03Tibremciclib：后发突围的“精调”CDK4/6抑制剂• Tibremciclib获批经历乳腺癌领域的CDK4/6抑制剂早已形成全球三巨头格局：辉瑞的Ibrance、诺华的Kisqali、礼来的Verzenio。这类药物通过抑制细胞周期蛋白的活性，延缓HR阳性、HER2阴性乳腺癌的进展。此次由贝达药业 (Betta Pharma) 开发的tibremciclib，作为中国本土第八款同类药物，却并非简单复制。在一项中国III期临床研究中，tibremciclib联合fulvestrant用于激素治疗耐药患者，显著延长无进展生存期（PFS），将疾病进展或死亡风险降低69%。与Verzenio相似，tibremciclib也为可口服制剂，但在分子设计上对CDK9的抑制力更弱，可能减少常见的不良反应，如脱发和造血抑制。• Tibremciclib获批意义Tibremciclib 的批准，是对“精调式药物优化”的一次有效示范。CDK4/6 类药物自诞生以来已积累大量数据与经验，但非选择性抑制仍导致一定比例的骨髓抑制、肠道不适等毒副反应，特别是在亚洲女性患者中更为显著。Tibremciclib 通过在结构上降低对CDK9的亲和性，使其在确保肿瘤控制力的同时，可能减少脱发与造血系统毒性。这种选择性提高+耐受性优化的方向，正在成为后CDK4/6时代的国际共识。其III期数据的强劲表现，不仅巩固了中国本土产品的竞争地位，也为全球CDK4/6领域提供了一个新范例。尤其是在多国CDK4/6研发布局拥挤的当下，tibremciclib若能在亚洲乃至拉美、非洲等市场推进，或可重塑全球此类药物的定价与组合策略。从患者角度出发，它则带来了延长PFS的可能性，以及一款更适合长期治疗、日常生活影响更低的方案。对于中老年HR+/HER2-女性而言，这种治疗体验的改善尤为重要。TONACEA04Suvemcitug：重构抗血管生成治疗的卵巢癌版图• Suvemcitug获批历程抗VEGF治疗在多个肿瘤中早已被证实有效，Avastin（Bevacizumab）作为老牌抗体药物也被广泛用于卵巢癌。但在铂耐药这一高度未满足的患者群体中，国际上尚未取得明确的突破。由先声药业开发的人源化IgG1型抗VEGF单抗药物suvemcitug，选择从这一人群切入，并在中国开展随机III期临床试验Scores，获得显著成果。数据显示，suvemcitug联合化疗使患者疾病进展或死亡风险降低54%，并在总生存期方面展现出21%的初步风险降低。这是目前全球首个在“铂耐药卵巢癌”中由双盲RCT支持的抗血管生成治疗证据，为这一人群提供了新的治疗策略，也为中国原创抗体药物拓展全球路径提供了范例。• Suvemcitug获批意义Suvemcitug 所代表的，不仅是一种新抗VEGF药物，更是一种高选择性新适应症的临床策略。在铂耐药卵巢癌这一极具挑战的群体中，传统疗法几乎束手无策，且大部分患者属于既往反复治疗后的虚弱体质，对毒性忍耐度更低。suvemcitug 的成功，不仅在于其数据的显著性，更在于它作为国产生物药，首次在一个由国际大厂长期主导的靶点领域打出了差异化临床证据。其III期Scores研究是首个在该适应症中使用双盲设计的抗血管生成药试验，严格性远高于以往开放标签研究，也为其未来寻求FDA或EMA认可以及跨境许可合作提供了有力基础。对患者而言，这不仅仅是多一种药，更是从无到有的希望。对于年均OS不足12个月、且治疗选择匮乏的铂耐药卵巢癌患者来说，suvemcitug 不只延长生存，更可能延缓生活质量急剧恶化的过程。TONACEA05Firsekibart：在痛风治疗中填补“生物制剂空白”• Firsekibart获批历程急性痛风发作虽属常见炎性疾病，但对传统药物不耐受或有禁忌者，治疗手段极为有限。Firsekibart由长春金赛药业（Changchun GeneScience Pharmaceutical）开发，是一款靶向IL-1β的人源化单克隆抗体，与诺华的Ilaris机制相同。2023年Ilaris获得FDA批准用于急性痛风发作，但尚未在中国上市。Firsekibart则率先满足中国患者在生物制剂治疗方面的临床空白。它适用于不能耐受NSAIDs (非甾体抗炎药)、秋水仙碱，且不宜反复用糖皮质激素的特定患者群体，体现出高度精准的患者定位策略。• Firsekibart获批意义痛风是一种常见病中的严重病，尤其是在高尿酸人群不断扩大的当下，其急性发作对生活的干扰、对慢病共病（如心血管、糖代谢）的影响正受到临床高度重视。而传统的NSAIDs与秋水仙碱方案，对肾功能不全、老年人群乃至合并用药的患者群体已不再适用。Firsekibart 的出现，首次将炎症源头阻断引入这一领域。IL-1β 是痛风发作中关节急性炎症的关键因子，其作用远早于症状出现阶段。Firsekibart 的靶向机制，可在症状高峰前介入，从机制上抑制炎症级联反应，真正做到了对因治疗，而非传统解热镇痛的对症处理。全球市场上，Ilaris 虽已在美国等国获批，但因价格昂贵和适应症局限，且未在更多的国家落地。Firsekibart 不仅为中国本地患者提供了可及选择，也有望以“定价合理+患者精准识别”的优势，在新兴市场建立自己的生态。TONACEA06中国新药的全球接轨，进入“机制输出”时代这四款新药的集中批准，并非偶然巧合，而是中国医药产业从结构积累迈向全球输出的一个重要信号。我们正在见证一种转变：中国不再只是追逐国际标准的执行者，而逐步成为临床机制和治疗策略的制定者（表1）。表1. 中国近期四款获批药物全球对照表Ifupinostat 不仅开创了全球靶点组合的新局面，也打通了免疫疗法后用药的缺口；tibremciclib 用优化结构向世界证明，创新不必大刀阔斧，也可以精雕细琢；suvemcitug 在铂耐药卵巢癌中所释放出的信号，将推动全球对VEGF类药物的适应症再认知；而 firsekibart，则真正将源头治疗理念带进了一个多年未有突破的常见疾病领域。这些突破，最终都将回到一个最本质的问题：为患者带来了什么？答案是”选择自由”。是“失败后还有药可选”的局面，是“新药可负担”的解脱。这一切，正在从中国发生，并向世界传递新的答案。参考文献：1.ASCO 2025: Efficacy and safety of ifupinostat (BEBT-908) in combination with rituximab for relapsed/refractory diffuse large B-cell lymphoma: Results from an exploratory phase Ib study. Retrieved on 03. 07. 2025.2.Zhang, L. et al. A phase I dose-escalation and dose-expansion study of tibremciclib, a novel CDK4/6 inhibitor, monotherapy and in combination with fulvestrant in HR-positive/HER2-negative advanced breast cancer. EMSO Open. 2025, 10.3.Dou, Z. et al. Safety and Efficacy of the First Subcutaneous ICI, Envafolimab, in the Treatment of Advanced Lung Cancer Patients: A Real-World Study. Thorac Cancer. 2025, 16, e70101.4.Xue, Y. et al. POS1177: EFFICACY AND SAFETY OF FIRSEKIBART IN ACUTE GOUTY ARTHRITIS: A MULTICENTRE, RANDOMIZED, DOUBLE-BLIND, DOUBLE-DUMMY, ACTIVE-CONTROLLED PHASE III STUDY. Annals of the Rheumatic Diseases. Volume 84, Supplement 1, 2025, Pages 1246-1247.5.Liu, A. China approves 4 new drugs, including a global first-in-class medicine. Fierce Pharma. 02. 07. 2025.

ASCO会议免疫疗法临床结果细胞疗法临床3期

2025-07-02

·FiercePharma

China approves 4 new drugs, including a global first-in-class medicine

As the domestic biotech industry matures, China has given birth to increasingly more first-in-class drug assets, some of which have become sources for global innovation. China’s National Medical Products Administration (NMPA) has approved four new drugs developed by local biopharma companies, including a first-of-its-kind molecule in blood cancer.Wednesday, Chinese regulators announced (Chinese) the conditional approval of ifupinostat (BEBT-908) for treating diffuse large B-cell lymphoma (DLBCL) patients who have tried at least two prior lines of therapy.The drug, developed by BeBetter Med, is now the first HDAC/PI3K dual-targeted inhibitor approved anywhere, even though the U.S. FDA has approved multiple drugs separately targeting the two types of enzymes in blood cancers.Massachusetts-based Curis had previously been working on an HDAC/PI3K candidate called fimepinostat, which in 2018 earned an FDA “Fast Track” designation in third-line DLBCL. But the company shelved the program to put all its resources behind emavusertib, a potential first-in-class IRAK4 inhibitor, also in B-cell malignancies.A novel mechanism doesn’t necessarily mean better efficacy. In a pivotal phase 2b study, ifupinostat yielded an overall response rate (ORR) of 33.8%, according to BeBetter. After excluding patient loss to follow-up and protocol deviations caused by the COVID-19 pandemic, the ORR was 53.6%. But the number is lower than the roughly 70% posted by Gilead Sciences’ CD19 CAR-T therapy Yescarta in the Zuma-1 trial. Importantly, cross-trial comparisons come with intrinsic flaws such as differences in baseline patient characteristics.Nevertheless, ifupinostat delivered an adjusted 67% ORR in patients who had failed CAR-T and bispecific antibodies, according to BeBetter.Besides, as a small molecule drug, ifupinostat will be priced significantly cheaper than CAR-T and T-cell engagers, BeBetter noted.The company is conducting a confirmatory phase 3 trial to turn ifupinostat’s conditional nod into a full approval. The study is combining ifupinostat with rituximab in second-line DLBCL. In an exploratory phase 1b study, the combo achieved a 76.2% ORR as second-line treatment, according to results presented at this year’s American Society of Clinical Oncology meeting.As China's biotech industry matures, the country has given birth to an increasing number of first-in-class drug assets, some of which have become sources for global innovation. These include Akeso’s ivonesimab, which in 2024 became the world’s first approved PD-1xVEGF bispecific antibody thanks to a Chinese nod in EGFR-mutated nonsquamous non-small cell lung cancer.The PD-(L)1xVEGF mechanism gained prominence after ivonescimab’s phase 3 head-to-head success against Merck & Co.’s Keytruda in a Chinese population of patients with first-line NSCLC. Merck, Bristol Myers Squibb and Pfizer have since added to the fanfare with potential multibillion-dollar licensing deals all surrounding candidates developed in China. Also on Wednesday, the NMPA cleared China’s eighth CDK4/6 inhibitor, Betta Pharma’s tibremciclib, to be used alongside fulvestrant in HR-positive, HER2-negative breast cancer following progression on endocrine therapy. The drug has a similar structure to Eli Lilly’s Verzenio but with less inhibition of CDK9.In a China phase 3 trial, the addition of tibremciclib to fulvestrant led to a 69% reduction in the risk of progression or death compared with fulvestrant alone.In a third new cancer drug approval by NMPA, the agency greenlighted Simcere’s anti-VEGF antibody suvemcitug for use alongside chemotherapy for ovarian cancer patients who have tried no more than one line of therapy after developing resistance to platinum-based chemo.The drug proved its worth in a China phase 3 trial coded Scores carried out in patients with platinum-resistant ovarian cancer. Patients in the suvemcitug arm had a 54% lower chance of progression or death versus those in the placebo group, according to data released at least year’s ASCO meeting. Overall survival data were immature but favored the suvemcitug arm with a preliminary 21% death risk reduction.At that time, investigators noted that Scores was the first double-blinded phase 3 trial demonstrating the efficacy of an anti-angiogenic agent in platinum-resistant ovarian cancer. Outside of oncology, the NMPA cleared Changchun GeneScience Pharmaceutical’s firsekibart (formerly genakumab) for certain patients with acute gouty flares. To be eligible, patients must be unable to tolerate or respond to non-steroidal anti-inflammatory drugs and colchicine, and they must not be suitable to receive steroid hormones repeatedly.The drug blocks IL-1β, the same target of Novartis’ Ilaris, which secured its own gout flares nod from the U.S. FDA in 2023, making it the first biologic therapy in the indication. Ilaris is not approved in China.

临床结果临床3期临床2期免疫疗法上市批准

2024-03-08

·生物谷

清华大学郗乔然课题组与天坛医院合作开发针对H3.3K27M突变型弥漫内生型脑桥胶质瘤的治疗方案

弥漫内生型脑桥胶质瘤（Diffuse Intrinsic Pontine Gliomas，DIPG）是一种儿童脑肿瘤，具有高度侵袭性、难以手术治疗、死亡率高的特点，目前尚无有效的治疗方法。研究表明，约80%的DIPG患者存在组蛋白H3K27M突变，导致全基因组H3K27me3的降低和转录异常，该突变被认为是DIPG发病的主要推动因素。尽管目前新型治疗药物主要集中在调节组蛋白甲基化和乙酰化平衡状态，以修复由H3K27M突变引起的级联效应，但由于临床转化效果不佳，DIPG仍然需要新的治疗方案。除了H3K27M突变外，90%的H3.3K27M型DIPG存在p53信号通路异常，包括TP53自身突变（占比65%~69%）和PPM1D突变（占比20%~28%）。PPM1D突变可降低p53的稳定性，使其失活，从而促进DIPG的肿瘤进展。这表明重新激活p53的抑癌功能可能是DIPG的潜在治疗靶点。2024年2月15日，清华大学生命学院郗乔然课题组与首都医科大学附属北京天坛医院张力伟课题组合作，在《癌症研究》（Cancer Research）杂志上发表题为“Fimepinostat通过抑制NFκB和PI3K/AKT信号增强吉西他滨对H3K27M突变型弥漫内生型脑桥胶质瘤的治疗效果”（Fimepinostat impairs NFκB and PI3K/AKT signaling and enhances gemcitabine efficacy in H3.3K27M-diffuse intrinsic pontine glioma）的研究论文，系统性地阐述了吉西他滨在H3.3K27M突变型DIPG中的作用机制，并提出了吉西他滨与Fimepinostat联合用药的治疗策略。该研究通过对多株DIPG原代细胞系，利用药物筛选确认吉西他滨作为潜在治疗药物。研究验证了吉西他滨能有效抑制DIPG在体外和小鼠体内的肿瘤形成，并揭示了吉西他滨引起DNA损伤、激活p53以及增加p53对凋亡相关基因的调控可及性，从而诱导细胞凋亡。此外，研究还发现吉西他滨在H3K27M存在的条件下诱导DIPG的细胞凋亡。然而，吉西他滨在引起DNA损伤的同时，也激活内源性逆转录病毒元件（Endogenous retrovirus，ERV），并激活cGAS-STING信号及下游RELB介导的非经典NF-κB信号通路，从而促使肿瘤存活。再次进行药物筛选后，研究发现Fimepinostat与吉西他滨表现出卓越的药物协同性，且Fimepinostat能够抑制吉西他滨激活的非经典NF-κB信号通路，同时阻断PI3K/AKT信号通路，产生持续的DNA损伤效应，表现出在体外和体内实验中的卓越协同抗肿瘤作用。图：使用吉西他滨重新激活p53的肿瘤抑制功能联合Fimepinostat抑制非经典NF-κB信号和PI3K/AKT信号，可能是治疗H3.3K27M突变的DIPG患者的潜在治疗方案清华大学生命学院郗乔然副教授、首都医科大学附属北京天坛医院张力伟教授为论文共同通讯作者。清华大学2018级已毕业博士生王丹为本文的第一作者。清华大学生命学院郗乔然课题组2016级已毕业博士生闫坤、2020级博士生余红杏、2019级本科生李浩成、2019级博士生周威及2019级硕士生郭书凝参与了本文部分实验工作。上海交通大学唐玉杰教授为本研究提供了部分DIPG细胞系。清华大学生命科学学院刘念副教授及其课题组的博士后洪雅强为本课题提供了转座子分析，清华大学生命科学学院吴畏教授为本课题提供了表观遗传类小分子化合物库。首都医科大学附属北京天坛医院王一、徐骋和泮长存提供了研究需要的临床样本和信息。本研究得到了国家自然科学基金、科技部国家重点研发计划、北京市自然科学基金和清华-北大生命科学联合中心的大力支持。论文链接：https://doi-org.libproxy1.nus.edu.sg/10.1158/0008-5472.CAN-23-0394原文链接：https://life-tsinghua-edu-cn.libproxy1.nus.edu.sg/info/1131/5582.htm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！

临床结果

100 项与 Fimepinostat 相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D11319	Fimepinostat	-	DB11891

研发状态

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
甲状腺未分化癌	临床2期	美国	National Cancer Institute	2016-12-22
分化型甲状腺癌	临床2期	美国	National Cancer Institute	2016-12-22
甲状腺低分化癌	临床2期	美国	National Cancer Institute	2016-12-22
弥漫性大B细胞淋巴瘤	临床2期	美国	Curis, Inc.	2016-07-01
复发性弥漫性大B细胞淋巴瘤	临床2期	美国	Curis, Inc.	2016-07-01
复发性弥漫性大B细胞淋巴瘤	临床2期	西班牙	Curis, Inc.	2016-07-01
复发性胶质母细胞瘤	临床1期	美国	Curis, Inc.	2019-08-07
复发性胶质母细胞瘤	临床1期	瑞士	Curis, Inc.	2019-08-07
复发性恶性胶质瘤	临床1期	美国	Curis, Inc.	2019-08-07
复发性恶性胶质瘤	临床1期	瑞士	Curis, Inc.	2019-08-07

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临床结果

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


NCT02674750 (CTgov)	临床2期	弥漫性大B细胞淋巴瘤 \| 复发性弥漫性大B细胞淋巴瘤	70	CUDC-907 (Group A)	艱艱廠範襯觸壓艱襯襯(獵鑰繭膚鹽艱鹹廠壓淵) = 鏇獵築觸網鹽鹹選網選網範繭衊艱醖壓顧餘鏇 (觸夢鹽餘鑰鹽獵鏇製製, 憲積蓋廠構壓鏇壓蓋選 ~ 築壓餘獵鹽醖顧壓醖繭) 更多	-	2022-04-27
				CUDC-907 (Group B)	艱艱廠範襯觸壓艱襯襯(獵鑰繭膚鹽艱鹹廠壓淵) = 醖鹽構繭夢淵壓鏇膚蓋網範繭衊艱醖壓顧餘鏇 (觸夢鹽餘鑰鹽獵鏇製製, 蓋膚鑰繭網鹹襯廠構糧 ~ 遞襯餘繭膚鑰膚襯鹽壓) 更多
NCT01742988 (ASCO 12020 \| ASCO 22020) 人工标引	临床1期	B细胞淋巴瘤	16	fimepinostat+venetoclax	網夢鏇鏇繭窪構願夢齋(壓窪網製觸襯蓋餘衊選) = 69%[4 pts (25%) had SAEs considered related to either F or V.] 簾憲鏇願遞鏇餘鏇夢糧 (憲構鹽製蓋遞積獵襯鹹 ) 更多	积极	2020-05-29
NCT01742988 (CUDC-907-101, ICML2019)	临床1/2期	难治性淋巴瘤 MYC \| BCL2	42	Fimepinostat 30 mg daily + Venetoclax 400 mg QD	衊鑰艱獵餘窪鹹鬱廠齋(衊範膚窪襯製繭窪夢構) = 廠壓築鏇糧鏇鏇襯壓憲積糧淵艱淵醖淵顧鹽壓 (蓋膚繭願淵鬱選憲膚憲 )	积极	2019-06-12
				Fimepinostat 60 mg daily + Venetoclax 400 mg QD	衊鑰艱獵餘窪鹹鬱廠齋(衊範膚窪襯製繭窪夢構) = 觸艱鬱鑰觸觸觸築鏇糧積糧淵艱淵醖淵顧鹽壓 (蓋膚繭願淵鬱選憲膚憲 )
NCT01742988 (Pubmed)	临床1期	复发性弥漫性大B细胞淋巴瘤	37	CUDC-907 monotherapy	獵繭餘顧壓顧膚膚顧廠(積壓衊網窪醖鏇夢觸築) = 願醖鹽鹽蓋艱獵遞選蓋選憲繭範鹽鹹願獵範遞 (壓夢願糧網艱顧糧窪製 ) 更多	-	2017-11-01
				CUDC-907 with rituximab	獵繭餘顧壓顧膚膚顧廠(積壓衊網窪醖鏇夢觸築) = 願廠構糧衊築願鑰糧範選憲繭範鹽鹹願獵範遞 (壓夢願糧網艱顧糧窪製 ) 更多
NCT02909777 (ASCO2017)	临床1期	实体瘤 \| 中枢神经系统肿瘤 \| 淋巴瘤	44	CUDC-907	艱鹽夢獵淵壓壓齋繭積(遞蓋衊範獵築窪夢遞觸) = 襯夢鑰繭鏇餘窪醖憲簾襯製衊壓構製願餘築構 (艱蓋鑰築鬱繭壓襯壓觸 )	-	2017-05-30
NCT01742988 (Pubmed \| Lancet Oncol) 人工标引	临床1期	多发性骨髓瘤 \| 淋巴瘤	44	CUDC-907	蓋願繭窪網鏇鹽蓋鬱製(築顧齋餘醖鑰繭顧淵壓) = 60 mg on the 5/2 dosing schedule 齋簾夢艱選觸遞膚憲顧 (繭廠糧繭鑰鬱觸鏇網觸 ) 更多	积极	2016-05-01
CUDC-907 (ICML2015)	临床1期	多发性骨髓瘤 \| 难治性淋巴瘤	51	CUDC-907 30mg	築蓋願築觸窪衊觸廠憲(構網夢糧範醖選齋鹽衊) = 淵積範鹽鬱窪窪鏇淵製憲獵遞糧廠遞鬱鑰網衊 (鏇艱築夢積獵鑰鹽壓構 ) 更多	积极	2015-06-09
				CUDC-907 60mg	築蓋願築觸窪衊觸廠憲(構網夢糧範醖選齋鹽衊) = 獵鏇鹽夢鏇衊遞積顧鹽憲獵遞糧廠遞鬱鑰網衊 (鏇艱築夢積獵鑰鹽壓構 ) 更多