The goal of this clinical trial is to determine how well people tolerate treatment with alisertib at different doses when it is used together with paclitaxel to treat people with SCLC. The main question it aims to answer is:
* What percentage of side effects, both mild and serious, do participants experience when being treated with alisertib and paclitaxel based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 (NCI CTCAE v.5.0)?
The study will consist of different groups, called cohorts, in which alisertib will be studied at increasing doses. Participants in the first group, Cohort 1, will take 30 mg of alisertib by mouth 2 times a day. The dose will increase by 10 mg 2 times a day for each new cohort of participants joining the study. Side effects will be checked during the study, and the decision to increase the dose of alisertib will be based on the specific side effects experienced during the first 21 days of treatment for each cohort.
Participants will:
* take alisertib by mouth on their own 2 times a day from Day 1 through Day 7 of each 21-day cycle and will be given paclitaxel intravenously at a dose of 60 mg/m2 on Day 1 and Day 8 of each 21-day cycle.
* be given a preventive treatment to increase their body defenses, called granulocyte-colony stimulating factor (G-CSF). Study staff will give G-CSF after the last dose of alisertib or paclitaxel of each 21-day cycle in which alisertib was given.
* provide blood samples to evaluate the different levels of alisertib in the blood at different times. Blood samples will be collected on Days 1 and 7 of the first and second 21-day cycles of treatment.
* be treated with alisertib and paclitaxel until death, worsening of the disease, unacceptable toxicity, unwillingness to continue participating in the trial, or other criteria that requires participants to stop treatment and participation in the study.
* be contacted every 8 weeks after stopping alisertib and paclitaxel treatment as part of a specific study phase called the long-term follow-up period. This will last until death, unwillingness to continue participating in the trial, or until the end of the study.

开始日期2026-09-30

申办/合作机构

Puma Biotechnology, Inc.

NCT07706179

/ Not yet recruiting临床2期IIT

Targeting Aurora A Kinase to Overcome Treatment Resistance in Advanced HR+/HER2+ Breast Cancer: A Biomarker-Driven Pilot Clinical Trial

The goal of this clinical trial is to learn if alisertib in addition to usual care works to treat HR+/HER2+ breast cancer. The main questions it aims to answer are:
* Does alisertib stop the communication between HR and HER2?
* Are there genetic markers that predict how well someone's cancer will respond to alisertib?
Participants will receive alisertib in addition to their usual care.

开始日期2026-09-01

申办/合作机构

University of Wisconsin-Madison

NCT06369285

/ Recruiting临床2期

A Phase 2 Study of Alisertib in Combination With Endocrine Therapy in Patients With HR+, HER2-negative Recurrent or Metastatic Breast Cancer

PUMA-ALI-1201 is a randomized, dose optimization, multicenter, Phase 2 study of alisertib administered in combination with endocrine therapy in participants with pathology-confirmed HR-positive/HER2-negative metastatic breast cancer (MBC) following progression on or after at least two prior lines of endocrine therapy in the recurrent or metastatic setting. This study is intended to evaluate the optimal alisertib dose administered in combination with the selected endocrine therapy. The study is also planned to evaluate the efficacy, safety, and pharmacokinetics of alisertib in combination with endocrine and to identify the biomarker-defined subgroup(s) that may benefit most from combined alisertib and endocrine therapy. Participants randomized prior to Amendment 4 are randomized 1:1:1 to Arm 1, Arm 2 or Arm 3. Participants randomized under Amendment 4 will be randomized 1:1 to Arm 1 or Arm 2.

开始日期2024-11-19

申办/合作机构

Puma Biotechnology, Inc.

100 项与 Alisertib 相关的临床结果

登录后查看更多信息

100 项与 Alisertib 相关的转化医学

登录后查看更多信息

100 项与 Alisertib 相关的专利（医药）

登录后查看更多信息

600

项与 Alisertib 相关的文献（医药）

2026-09-01·Veterinary and Comparative Oncology

Comparative Response of Canine and Human Osteosarcoma Tumour Cell Lines to Molecularly Targeted Anticancer Agents at Clinically Relevant Exposures With Analysis of Genomic Biomarkers

Article

作者: Duval, Dawn L. ; Gustafson, Daniel L. ; Early, Kala A. ; Poplawski, Klaudia A. ; Das, Sunetra ; Morales, Maritza A.

ABSTRACT:

Osteosarcoma (OSA) is a primary bone tumour occurring in children but is also prevalent in large breed dogs. Canine OSA (cOSA) has long been viewed as analogous to human OSA (hOSA) with cOSA serving as a surrogate for development of therapeutic approaches to treat the rarer human form. Drug therapy of OSA has remained virtually unchanged over the last four decades and drug testing is challenging due to the genomic heterogeneity of OSA as well as the limited number of patients for clinical trials. Thus, an approach that includes a suitable clinical surrogate at the early stage of therapeutic development may be beneficial. Therefore, to address these challenges, a phenotypic drug screen of 12 targeted anticancer drugs was carried out using 13 cOSA and 6 hOSA cell lines and responses compared at clinically relevant exposures (CRE) estimated from human data. The results identified four drugs (alisertib, crizotinib, onvansertib and sorafenib) with significant responses at the CRE in cOSA and hOSA cell lines and demonstrated that drug responses were indistinguishable across species. Correlations of drug response with genomic biomarkers in the cOSA cell line panel identified Myc and Hedgehog signalling as potential predictors of crizotinib response and Myc, epithelial markers and anti‐apoptotic signalling for onvansertib response. The conclusions of these findings are that cOSA and hOSA cell lines show the same range of response to targeted agents and identify potential biomarker pathways for further investigation in OSA tumours for use in future comparative oncology studies including clinical trials in pet dogs.

2026-07-02·MOLECULAR CANCER THERAPEUTICS

Chromobox 2 Inhibition: A Novel Activity of Alisertib, an Aurora A Kinase Inhibitor

Article

作者: Nurmemmedov, Elmar ; Bitler, Benjamin G. ; Elder, Alan M. ; Petkov, Alexander ; Reigan, Philip ; Woodruff, Elizabeth R. ; Brubaker, Lindsay W. ; Eisenmesser, Elan ; Yamamoto, Tomomi M. ; Iwanaga, Ritsuko

Abstract:

Chromobox 2 (CBX2), a subunit of polycomb repressor complex 1 (PRC1), is expressed in high-grade serous carcinoma (HGSC). CBX2-inhibitory peptide (CBX2i) has demonstrated efficacy in a syngeneic mouse model but has limitations. We sought to identify an alternative approach to CBX2 inhibition. A computational-based molecular docking screen was performed using the Selleckchem Bioactive Library to identify inhibitors of CBX2. A similarity screen of top hits against the bound conformation of CBX2i pharmacophore model was performed in parallel. A series of in vitro validation studies evaluated the effect of alisertib on proliferation, a CBX2 target gene, and stemness. CBX2-knockdown cell lines and a syngeneic murine model were utilized to evaluate alisertib response in the context of CBX2 loss. Cell target engagement assay was performed. PRC1 activity was measured by H2AK119ub levels. Immune profiling of treated tumors defined the immune microenvironment. The computational-based screen identified 10 candidate compounds. In vitro validation narrowed compounds of interest to raltitrexed, alisertib, GTX-007, LY315920, and PD0325901. Ultralow dilution assay demonstrated a dramatic decrease in spheroid formation with alisertib, an aurora A kinase (AURKA) inhibitor. Good structural overlap was observed between CBX2i and alisertib. Cell target engagement assay confirmed alisertib selectivity for both AURKA and CBX2. Loss of CBX2 attenuated alisertib efficacy in vitro and in vivo. Treatment with alisertib leads to a decrease in H2AK119ub and shift in the immune tumor microenvironment. Alisertib efficacy in HGSC is dependent on functional CBX2, and cell target engagement confirms selectivity for CBX2, supporting that alisertib activity involves CBX2 inhibition.

2026-07-01·PHYTOMEDICINE

Tongguanteng injection induces cell cycle arrest and drives ferroptosis through AURKA/KEAP1/NRF2 axis in breast cancer

Article

作者: Liang, Hanlu ; Guo, Cheng ; Chen, Junjun ; Shi, Meizhi ; Ding, Qixuan ; Hu, Yujie ; Zhou, Yangyun ; Zhang, Xiangqi ; Han, Yonglong ; Zhao, Shuai ; Chen, Jiayi ; Zhang, Jingxian ; Xu, Lingyan ; Yang, Jiao

BACKGROUND:

Tongguanteng Injection (TGT), derived from the stems of Marsdenia tenacissima, has been demonstrated to exert anti-tumor effects. Aurora Kinase A (AURKA) is a key regulator of cell cycle progression and has become a promising target for breast cancer treatment. However, the role of AURKA in ferroptosis is unclear, particularly regarding its contribution to the therapeutic effect of TGT in breast cancer.

METHODS:

The chemical components of TGT were analyzed by Ultra-high performance liquid chromatography coupled with hybrid quadrupole-orbitrap high resolution mass spectrometry (UHPLC-Q-Orbitrap HRMS). The anti-breast cancer effect of TGT were detected in vitro and in vivo. RNA-seq analysis were used to identify the targets of TGT treatment. Subsequently, flow cytometry, RT-PCR, western blot, Co-IP, immunofluorescence and immunohistochemistry were employed to elucidate the regulatory mechanisms of TGT on ferroptosis and cell cycle. Concurrently, ferroptosis and cell cycle associated pathways were investigated in the plasmids and siRNAs transfected cells. Furthermore, tumor bearing mouse model was established by 4T1 cells stably transduced with lentivirus for further validating the findings.

RESULTS:

A total of 136 compounds were identified from TGT. The study demonstrates that TGT exerts an anti-breast cancer effect by inducing G2/M phase arrest and ferroptosis, evidenced by downregulation of CDK1 and Cyclin B, as well as increased Fe²⁺ accumulation, glutathione (GSH) depletion, and elevated lipid peroxidation. RNA-seq analysis revealed that AURKA was significantly downregulated and identified as a key target of TGT treatment. Mechanistically, TGT disrupts the AURKA-Kelch-like ECH-associated protein 1 (KEAP1) interaction, leading to nuclear factor E2-related factor 2 (NRF2) nuclear translocation and subsequent heme oxygenase 1 (HO-1)-mediated ferroptosis in vitro. Knockdown of AURKA or treatment with its inhibitor alisertib both induce G2/M phase arrest and ferroptosis, while AURKA overexpression reverses the effects of TGT and accelerates tumor progression. Combining TGT with docetaxel enhances ferroptosis sensitivity and amplifies the regulatory effect of AURKA on cell cycle and ferroptosis. Consistent with in vitro results, TGT significantly inhibited tumor growth, arrested cell cycle and promoted ferroptosis in 4T1-AURKA^LV cell bearing mice.

CONCLUSION:

These findings propose that TGT targets AURKA/KEAP1/NRF2 axis to exert anti-breast cancer effect, and AURKA inhibition represents a potential strategy for breast cancer treatment through inducing cell cycle arrest and driving ferroptosis.

112

项与 Alisertib 相关的新闻（医药）

2026-09-09

·BioSpace

Puma Biotechnology to Present at H.C. Wainwright’s 28th Annual Global Investment Conference

LOS ANGELES--(BUSINESS WIRE)--Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, announced that Alan H. Auerbach, Chairman, Chief Executive Officer, President and Founder, will provide an overview of Puma at 3:30 p.m. ET on Monday, September 14, at the H.C. Wainwright 28th Annual Global Investment Conference. The conference will be held September 14-16, 2026 at the Lotte New York Palace Hotel in New York City. A live webcast of the conference call and presentation slides may be accessed on the Investors section of the Puma Biotechnology website at . The presentation will be archived on the website and available for 30 days. About Puma Biotechnology Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licensed the global development and commercialization rights to PB272 (neratinib, oral) in 2011. Neratinib, oral was approved by the U.S. Food and Drug Administration in 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX ® (neratinib) tablets. In February 2020, NERLYNX was also approved by the FDA in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. NERLYNX was granted marketing authorization by the European Commission in 2018 for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year from completion of prior adjuvant trastuzumab-based therapy. NERLYNX ® is a registered trademark of Puma Biotechnology, Inc. In September 2022, Puma entered into an exclusive license agreement for the development and commercialization of the anti-cancer drug alisertib, a selective, small molecule, orally administered inhibitor of aurora kinase A. Initially, Puma intends to focus the development of alisertib on the treatment of small cell lung cancer and breast cancer. In February 2024, Puma initiated ALISCA ® -Lung1, a Phase II clinical trial of alisertib monotherapy for the treatment of patients with extensive-stage small cell lung cancer. In November 2024, Puma initiated ALISCA ® -Breast1, a Phase II clinical trial of alisertib in combination with endocrine therapy for the treatment of patients with HER2-negative, HR-positive metastatic breast cancer. ALISCA ® is a registered trademark of Puma Biotechnology, Inc. Further information about Puma Biotechnology may be found at . Contacts Alan H. Auerbach or Mariann Ohanesian, Puma Biotechnology, Inc., +1 424 248 6500 info@pumabiotechnology.com ir@pumabiotechnology.com David Schull, Russo Partners, +1 212 845 4200 david.schull@russopartnersllc.com

2026-09-03

·BioSpace

Puma Biotechnology Reports Inducement Awards Under Nasdaq Listing Rule 5635(c)(4) - September 3, 2026

LOS ANGELES--(BUSINESS WIRE)--Puma Biotechnology, Inc. (NASDAQ: PBYI), a biopharmaceutical company, announced that on September 1, 2026, the Compensation Committee of Puma’s Board of Directors approved the grant of inducement restricted stock unit awards covering 33,550 shares of Puma common stock to five new non-executive employees. The awards were granted under Puma’s 2017 Employment Inducement Incentive Award Plan, which was adopted on April 27, 2017, and provides for the granting of equity awards to new employees of Puma. The restricted stock unit awards vest over a three-year period, with one-third of the shares underlying the award vesting on the first anniversary of the award’s vesting commencement date, September 1, 2026, and one-sixth of the shares underlying the award vesting on each six-month anniversary of the vesting commencement date thereafter, subject to continued service. The awards were granted as an inducement material to the new employees entering into employment with Puma, in accordance with Nasdaq Listing Rule 5635(c)(4). About Puma Biotechnology Puma Biotechnology, Inc. is a biopharmaceutical company with a focus on the development and commercialization of innovative products to enhance cancer care. Puma in-licensed the global development and commercialization rights to PB272 (neratinib, oral) in 2011. Neratinib, oral was approved by the U.S. Food and Drug Administration in 2017 for the extended adjuvant treatment of adult patients with early stage HER2-overexpressed/amplified breast cancer, following adjuvant trastuzumab-based therapy, and is marketed in the United States as NERLYNX ® (neratinib) tablets. In February 2020, NERLYNX was also approved by the FDA in combination with capecitabine for the treatment of adult patients with advanced or metastatic HER2-positive breast cancer who have received two or more prior anti-HER2-based regimens in the metastatic setting. NERLYNX was granted marketing authorization by the European Commission in 2018 for the extended adjuvant treatment of adult patients with early stage hormone receptor-positive HER2-overexpressed/amplified breast cancer and who are less than one year from completion of prior adjuvant trastuzumab-based therapy. NERLYNX ® is a registered trademark of Puma Biotechnology, Inc. ezstandalone.cmd.push(function () { ezstandalone.showAds(131); }); In September 2022, Puma entered into an exclusive license agreement for the development and commercialization of the anti-cancer drug alisertib, a selective, small molecule, orally administered inhibitor of aurora kinase A. Initially, Puma intends to focus the development of alisertib on the treatment of small cell lung cancer and breast cancer. In February 2024, Puma initiated ALISCA ® -Lung1, a Phase II clinical trial of alisertib monotherapy for the treatment of patients with extensive-stage small cell lung cancer. In November 2024, Puma initiated ALISCA ® -Breast1, a Phase II clinical trial of alisertib in combination with endocrine therapy for the treatment of patients with HER2-negative, HR-positive metastatic breast cancer. ALISCA ® is a registered trademark of Puma Biotechnology, Inc. Contacts Alan H. Auerbach or Mariann Ohanesian, Puma Biotechnology, Inc., +1 424 248 6500 info@pumabiotechnology.com ir@pumabiotechnology.com

上市批准引进/卖出临床2期

2026-08-30

·神母最新文献

神经母细胞瘤双重表观遗传靶向策略：从协同致死机制到临床转化

神经母细胞瘤是一种来源于神经嵴的外周神经系统肿瘤，也是儿童癌症相关死亡的重要原因之一。高危神经母细胞瘤患者在确诊时常已发生转移，并且容易产生耐药性。尽管该肿瘤的体细胞突变负荷相对较低，但由于反复出现的节段性染色体异常，其临床异质性十分显著。不良预后因素主要包括 MYCN 扩增、1p 或 11q 染色体缺失以及 17q 获得。近年来，多模式综合治疗虽提高了患者生存率，但约半数高危神经母细胞瘤患者最终仍死于疾病进展。近年来，研究逐渐认识到尽管神经母细胞瘤整体体细胞突变负荷较低，但其显著的临床异质性主要与反复出现的染色体结构异常及复杂的表观遗传调控网络相关。这些调控不仅影响DNA甲基化、组蛋白修饰及染色质结构，还深度参与肿瘤细胞状态转化，例如肾上腺能状态与间充质状态之间的可逆切换，从而驱动肿瘤进展与治疗逃逸。在这一背景下，表观遗传治疗逐渐从基础研究走向临床探索，涵盖DNMT、HDAC、EZH2及BET等多个关键靶点，并通过与化疗、放疗、免疫治疗及分子靶向药物的组合策略，展现出潜在的协同抗肿瘤效应。尤其是“双重表观遗传靶向”以及针对关键转录程序（如MYCN轴）的间接干预，为克服高危疾病的耐药性提供了新的思路。然而，现有证据也提示表观遗传治疗具有明显的情境依赖性，其疗效受剂量、组合方式及肿瘤生物学状态影响显著，单药策略在临床中往往疗效有限。因此，如何筛选有效的预测性生物标志物、理解肿瘤表观遗传动态演化，并设计合理的联合治疗方案，成为未来研究的关键方向。神经母细胞瘤表观遗传靶向策略图文视频解读近期，瑞典卡罗林斯卡(Karolinska)医学院儿童肿瘤及儿童外科的Diana Treis等系统梳理了神经母细胞瘤表观遗传治疗的机制基础与临床进展，重点讨论了联合治疗策略的科学依据及其转化潜力，为未来开展更精准、更有效的个体化治疗提供了理论框架。文章发表在 Epigenomics 上，我们一起来了解下。 https://doi.org/10.1080/17501911.2026.2671148 表观遗传调控促进侵袭性神经母细胞瘤表观遗传调控在神经母细胞瘤的侵袭性和治疗耐受中发挥重要作用。研究发现，该肿瘤存在复杂的表观遗传改变，包括 DNA 甲基化、组蛋白修饰、染色质重塑以及非编码 RNA 调控等，这些变化共同促进了肿瘤恶性进展和耐药形成。近年来，神经母细胞瘤被划分为两种主要细胞状态：一种是类似交感神经母细胞、对化疗较敏感的肾上腺能（Adrenergic, ADRN）状态；另一种是更具耐药性的、类似神经嵴细胞的间充质（Mesenchymal, MES）状态。这两种状态的维持与相互转化受到表观遗传调控因子的控制，如组蛋白修饰和染色质重塑。因此，肿瘤细胞可塑性、肿瘤内外异质性以及获得性耐药性，限制了单一靶向治疗的疗效。近年来很多文献会提到神经母细胞瘤的两种表型：治疗敏感的肾上腺素能细胞（ADRN，Adrenergic）和治疗耐药的间充质细胞（MES，Mesenchymal）。ADRN和MES属于前沿的、基于基因和分子特征的研究分型，与我们熟知的基于显微镜下细胞形态的临床分型完全不同。公认的标志性文献是R. Versteeg和J. van Nes等于2017年发表在 Nature Genetics 上的一篇题为“Neuroblastoma is composed of two super-enhancer-associated differentiation states （神经母细胞瘤由两种与超增强子相关的分化状态组成）”的研究论文（doi: 10.1038/ng.3899），后续很多团队对此展开了研究。当前对于这两种表型的分类还未形成共识。一般来说ADRN细胞更接近交感神经系统分化方向，表达一系列神经元相关转录因子（如PHOX2B、GATA3等）和分化标志。它们通常具有较高的增殖活性，但同时也更依赖既定的分化程序，因此对化疗、放疗以及靶向GD2的免疫治疗更敏感。临床上大多数“初诊时反应较好”的神经母细胞瘤，往往以ADRN状态为主导。 MES细胞则更接近未分化的神经嵴祖细胞或间充质样状态，表达如CD90、CD73等间充质相关标志，转录调控上依赖另一套网络（例如PRRX1、NOTCH相关通路）。MES细胞的核心特征不是“长得快”，而是适应性强：迁移能力增强、抗凋亡能力提高、对化疗和免疫治疗更耐受，同时更容易进入低增殖甚至“休眠”状态。两种表型之间可能发生转换。如我们公众号曾经介绍过一个St Jude的RBM39降解剂联合抗GD2免疫疗法的研究，在该研究中，RBM39降解剂Indisulam能够促进神经母细胞瘤系状态从MES到ADRN的显著转变，细胞GD2表达大幅提高，该联合疗法在体内试验中可实现持久完全缓解。基于这一背景，研究者开始探索多种表观遗传联合治疗策略，包括通过表观遗传药物增强放疗或化疗敏感性，以及与靶向药联合应用。其中，“双重表观遗传靶向”是指联合使用两种或以上表观遗传药物，以期产生协同抗肿瘤作用。值得注意的是，最新的 ACCELERATE 共识报告已将表观遗传联合治疗列为重点发展方向之一。尽管表观遗传药物因能够增强其他治疗方式并具有自身抗癌活性而受到越来越多关注，但其潜力尚未被充分发挥。目前，表观遗传治疗尚未纳入神经母细胞瘤的常规临床方案，而成人临床试验经验也表明，单一表观遗传治疗往往疗效有限。因此，有必要进一步开展基于机制的联合表观遗传治疗研究。相关文章：加速神经母细胞瘤药物研发：国际专家们怎么看？│第三届神经母细胞瘤药物开发战略论坛共识声明以DNA甲基化为靶点治疗神经母细胞瘤 DNA 异常甲基化是癌症的重要特征之一，可促进神经母细胞瘤的发生与进展。DNA 甲基转移酶抑制剂（DNMTi）如地西他滨（decitabine）和阿扎胞苷（azacitidine），主要通过去除被沉默抑癌基因启动子的甲基化发挥抗肿瘤作用，同时还能诱导 DNA 损伤反应并激活抗肿瘤免疫反应。DNMTi 是最早进入临床常规应用的表观遗传药物之一，在血液系统肿瘤中疗效较为显著，但实体瘤对其单药治疗通常反应有限。在神经母细胞瘤中，一项早期 I 期临床试验将地西他滨与阿霉素和环磷酰胺联合应用于复发/难治性患者，结果显示，可耐受剂量的地西他滨尚不足以在这些重度预处理患者中产生明确的客观缓解。因此，目前针对成人实体瘤的研究策略更加重视 DNMTi 与其他表观遗传调控剂或免疫治疗的联合应用。这种联合思路同样适用于神经母细胞瘤。近年来的临床前研究表明，例如 DNMTi 与 EZH2 抑制剂联用，可产生潜在的协同抗肿瘤效应。此外，伏立诺他与诱导分化药物异维甲酸的联合方案，也曾在两项针对复发/难治性神经母细胞瘤的 I 期研究中进行评估。虽然未观察到明确的客观缓解，但相当一部分患者获得了长期疾病稳定，提示该联合方案仍具有进一步研究价值。另一方面，正在进行的 INFORM2 I/II 期研究（NCT03838042）正在评估 PD-1 免疫检查点抑制剂纳武利尤单抗（nivolumab）联合 HDACi 恩替司他（entinostat）在儿童及青少年复发性肿瘤（包括神经母细胞瘤）中的疗效。针对神经母细胞瘤重要致癌驱动基因 ALK，已有临床前研究支持 ALK 抑制剂与 HDACi 联合应用可产生协同抗肿瘤效应，但这一“双重靶向”策略尚缺乏临床研究验证。相关文章：131-I-MIBG/Dinutuximab/伏立诺他联合治疗复发难治性神经母细胞瘤在临床试验中展现强抗肿瘤活性│NANT EZH2抑制作为增强神经母细胞瘤治疗的一种方法 EZH2（enhancer of zeste homolog 2）是一种重要的组蛋白甲基转移酶，也是神经母细胞瘤中研究较为深入的表观遗传治疗靶点之一。EZH2 通过抑制抑癌基因转录促进肿瘤发生，并在神经母细胞瘤中呈高表达，因此被认为是具有潜力的联合治疗靶点。研究发现，抑制 EZH2 可促使神经母细胞瘤细胞由更耐药的间充质（MES）状态向对治疗更敏感的肾上腺能（ADRN）状态转化，同时提高 GD2 的表达，从而增强肿瘤细胞对 GD2 靶向免疫治疗的敏感性。这提示 EZH2 抑制剂有望作为免疫治疗增敏策略。此外，EZH2 与 HDAC 可协同抑制抑癌基因表达，因此 EZH2 抑制剂与 HDAC 抑制剂（HDACi）联合应用在神经母细胞瘤及其他肿瘤中表现出明显的协同细胞毒作用。目前，EZH2 抑制剂他泽司他（tazematostat）已获得 FDA 批准，用于治疗复发性滤泡性淋巴瘤；其与 HDACi 贝林司他（belinostat）联合治疗复发/难治性淋巴瘤的协同作用也正在临床研究中（NCT05627245）。另外，一项针对神经母细胞瘤细胞的药物组合筛选研究，对 13 种表观遗传药物、靶向药及化疗药物进行两两组合比较，结果显示，同时抑制两种组蛋白甲基转移酶 EZH2 和 DOT1L 是效果最强的组合方案。总体而言，已有大量临床前证据支持 EZH2 抑制剂与多种治疗方式联合应用，尤其是与 GD2 靶向免疫治疗及 HDAC 抑制剂联用。因此，开展 EZH2 抑制联合治疗在神经母细胞瘤中的临床研究具有重要意义。表观遗传策略间接靶向神经母细胞瘤中的MYCN/MYC 约 25% 的神经母细胞瘤患者存在MYCN 基因扩增，而 MYCN 扩增是高危疾病和不良预后的强有力预测因素。由于直接抑制 MYCN 本身存在较大困难，研究者开始尝试通过表观遗传调控等方式间接抑制这一关键致癌驱动因子。其中一种策略是同时抑制组蛋白去乙酰化酶（HDAC）和磷脂酰肌醇 3-激酶（PI3K）。双重作用药物非美诺司他（fimepinostat）在 MYCN 扩增型神经母细胞瘤临床前模型中显示出显著抗肿瘤效果。然而，在后续 I 期临床研究中，纳入的 4 例MYCN 扩增患者均未获得客观缓解。尽管如此，其中一名患者疾病稳定持续长达 24 个月，这是该研究中最理想的治疗结果，对于复发性 MYCN 扩增型神经母细胞瘤而言仍具有一定意义。研究者认为，缺乏明显肿瘤缩小可能与药代动力学限制有关，例如剂量限制性毒性导致系统药物暴露不足，这也反映出将表观遗传策略真正转化为高危患者有效治疗方案所面临的挑战。另一方面，BET（bromodomain and extra-terminal domain）家族蛋白是调控 MYCN 和 MYC 等癌基因表达的重要表观遗传调控因子，因此 BET 抑制剂（BETi）已成为 MYCN 扩增型高危神经母细胞瘤的潜在治疗手段。虽然大量临床前研究结果令人鼓舞，但目前针对神经母细胞瘤的 BETi 临床研究仍较有限。一项莫利布赛（molibresib）的 I 期研究仅纳入 1 例神经母细胞瘤患者，其最佳疗效为疾病稳定。此外，BET 抑制剂 BMS-986158 和BMS-986378 也已在一项针对复发/难治性实体瘤或淋巴瘤儿童患者的 I 期临床试验（NCT03936465）中进行评估，目前研究结果尚未公布。然而，成人肿瘤临床研究表明，耐药性的产生可能限制 BETi 单药治疗的临床应用。因此，BETi 联合治疗策略逐渐成为研究重点。在神经母细胞瘤中，BETi 与多种靶向药联合均显示出良好的临床前前景，包括 ROCK1/2 抑制剂（RKI-1447）、MEK 抑制剂（曲美替尼，trametinib）、HDAC 抑制剂（帕比司他，panobinostat）、AURKA 抑制剂（阿利色替，alisertib）、PI3K 抑制剂（匹替利司，pictilisib）、CDK 抑制剂（迪纳西利布dinaciclib、米尔西利milciclib、YKL-5–124）、MDM2 抑制剂（CGM097）以及蛋白酶体抑制剂（卡非佐米carfilzomib）等。此外，多项临床前研究还发现，维甲酸与 BET 抑制剂（如 JQ1 和 I-BET151）联合应用可产生有益的协同作用，进一步支持了 BETi 联合治疗在神经母细胞瘤中的应用潜力。神经母细胞瘤的新兴表观遗传疗法除上述经典表观遗传靶点外，越来越多新的表观遗传调控因子也被认为是神经母细胞瘤联合治疗的潜在候选靶点。近期一项预印本研究显示，H3K23 乙酰转移酶抑制剂 PF-9363 可与维甲酸类药物产生协同作用，促进神经母细胞瘤细胞分化，同时提高 GD2 的表达，使肿瘤细胞对 GD2 靶向免疫治疗更加敏感。值得注意的是，其临床类似物 PF-07248144 已在乳腺癌 I 期临床研究中显示出令人鼓舞的结果，目前正在成人多种实体瘤中开展进一步评估（NCT04606446）。然而，在神经母细胞瘤细胞的药物联合筛选中，与维甲酸协同作用最强的药物实际上是H3K27 去甲基化酶 KDM6A/B 抑制剂 GSK-J4。除与维甲酸联合外，GSK-J4 还被发现可与 Wip1 抑制剂 SL-176 产生显著协同作用。Wip1 抑制剂能够解除对 DNA 损伤反应的抑制，因此两者联合有望增强肿瘤细胞对 DNA 损伤的敏感性。此外，curaxin 类药物CBL0137 代表了一类新型表观遗传治疗药物，其作用机制是靶向 DNA 与组蛋白之间的相互作用，从而破坏染色质稳定性。临床前研究已证实其对包括神经母细胞瘤在内的多种肿瘤具有抗癌活性。进一步研究发现，CBL0137 与 HDAC 抑制剂帕比司他联合时，在体内模型中可产生明显协同抗肿瘤效应，尤其是在免疫系统完整的条件下效果更加突出。这一发现提示，未来该联合方案还有望进一步与免疫治疗结合应用。结论高危神经母细胞瘤目前仍是临床治疗中的重大挑战，亟需开发能够克服治疗耐药性的有效策略。大量临床前研究表明，表观遗传药物在神经母细胞瘤治疗中具有重要潜力。然而，这类药物并不能被盲目使用，因为已有零星研究报道其不仅可能产生毒副作用，甚至可能诱导促转移效应。此外，表观遗传调控因子本身具有多效性和高度依赖具体生物学背景的特点，因此，表观遗传药物的应用应建立在可靠预测性生物标志物基础之上，以实现个体化和生物学导向的精准治疗。未来仍需进一步研究神经母细胞瘤在疾病进展过程中表观遗传改变的动态演化，以及这些变化对表观遗传治疗敏感性的影响，同时筛选更加有效的预测性标志物。鉴于表观遗传单药治疗普遍容易出现耐药，目前最具前景的策略是将针对表观遗传脆弱性的药物与化疗、放疗、免疫治疗及分子靶向治疗联合应用。未来的早期临床试验将有助于明确联合表观遗传治疗在神经母细胞瘤患者中的真实临床价值。

100 项与 Alisertib 相关的药物交易

登录后查看更多信息

外链

KEGG	Wiki	ATC	Drug Bank
D10085	Alisertib	-	DB05220

研发状态

10 条进展最快的记录,

后查看更多信息

适应症	最高研发状态	国家/地区	公司	日期
难治性外周T细胞淋巴瘤	临床3期	美国	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	澳大利亚	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	奥地利	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	白俄罗斯	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	比利时	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	巴西	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	保加利亚	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	加拿大	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	智利	Millennium Pharmaceuticals, Inc.	2012-06-11
难治性外周T细胞淋巴瘤	临床3期	捷克	Millennium Pharmaceuticals, Inc.	2012-06-11

登录后查看更多信息

临床结果

适应症

分期

评价

查看全部结果

研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


NCT06095505 (PUMA-ALI-4201, WCLC2026)	临床2期	小细胞肺癌	50	Alisertib 50 mg BID	顧鏇鹽顧餘壓鬱鹹憲淵(齋簾艱餘繭鹽憲齋網齋) = 壓糧襯積繭積範顧壓鹹顧鑰餘繭願獵繭淵壓蓋 (壓淵願艱鑰積齋選齋膚 ) 更多	积极	2026-09-12
SABCS2025	临床1/2期	ER阳性/HER2阴性乳腺癌 ER+/HER2-	126	Alisertib monotherapy	窪艱鹹鹹願繭製憲網襯(鹽膚顧觸壓醖鏇觸鹽獵) = hematologic AEs (neutropenia, leukopenia, and anemia), and fatigue. 夢夢齋鹹鏇艱製鏇襯範 (鏇範糧壓繭鬱膚憲壓獵 )	积极	2025-12-10
				Alisertib ± fulvestrant
SNO2025	临床2期	中枢神经系统横纹肌瘤一线	71	Alisertib + chemotherapy + focal radiotherapy (Stratum B1)	衊鑰願夢選壓鹹襯餘鹽(糧願鏇築製齋獵網窪願) = 顧壓夢憲選鹹壓壓積膚鏇醖鏇淵襯願繭齋餘顧 (夢鏇糧製獵鑰艱艱艱築 ) 更多	不佳	2025-11-19
				Alisertib + chemotherapy + radiotherapy (Stratum B2)	衊鑰願夢選壓鹹襯餘鹽(糧願鏇築製齋獵網窪願) = 壓簾築艱鏇鹽顧鹹廠鹽鏇醖鏇淵襯願繭齋餘顧 (夢鏇糧製獵鑰艱艱艱築 )
NCT06369285 (ALISCA-Breast1, ASCO2025)	临床2期	HR阳性/HER2阴性乳腺癌 RB1 \| MYC \| TP53 ... 更多	-	Alisertib 30 mg + Endocrine Therapy	鏇壓遞構鏇築衊遞淵遞(鹹艱構製觸遞壓鹹構鬱) = 鬱壓餘觸夢選鬱積艱壓顧簾齋憲糧廠顧製鹽鑰 (鹽膚齋簾憲鑰鬱鑰淵齋 ) 更多	积极	2025-05-30
				Alisertib 40 mg + Endocrine Therapy	鏇壓遞構鏇築衊遞淵遞(鹹艱構製觸遞壓鹹構鬱) = 膚憲壓糧膚顧廠網艱壓顧簾齋憲糧廠顧製鹽鑰 (鹽膚齋簾憲鑰鬱鑰淵齋 ) 更多
NCT04555837 (CTgov)	临床1/2期	转移性头颈部鳞状细胞癌 \| 头颈部鳞状细胞癌 \| 恶性实体肿瘤	24	Alisertib+Pembrolizumab (Phase I)	窪壓鹽觸襯壓餘衊鏇積 = 獵築壓網範餘衊鏇鬱窪鹹廠網鬱範顧廠糧蓋餘 (鹹觸襯醖艱繭遞膚鏇構, 齋憲築築窪壓襯窪鑰構 ~ 獵鏇選築選齋餘壓壓製) 更多	-	2024-12-16
				Alisertib+Pembrolizumab (Phase II)	糧繭夢壓選構廠餘艱糧 = 膚廠選醖鏇膚襯襯觸鏇積繭淵醖觸淵築艱淵積 (襯鹹簾窪壓鑰遞餘範網, 艱膚網鹽願鑰觸衊繭鏇 ~ 憲鑰醖積鹽網壓積觸顧) 更多
NCT02860000 (TBCRC041 \| MC1431, CTgov)	临床2期	局部晚期乳腺癌 \| 转移性乳腺癌 \| 激素难治性乳腺癌 ... 更多	96	Laboratory Biomarker Analysis+Alisertib (Arm I (Alisertib))	蓋鏇襯範糧觸窪膚鬱鹽 = 獵選鹽夢鏇鏇襯膚窪壓蓋膚壓網淵壓製壓夢鬱 (構齋積醖膚觸醖製糧鏇, 獵夢鑰夢齋廠製膚鏇齋 ~ 壓醖簾選繭簾壓憲淵壓) 更多	-	2024-10-18
				Laboratory Biomarker Analysis+Alisertib+Fulvestrant (Arm II (Alisertib, Fulvestrant))	蓋鏇襯範糧觸窪膚鬱鹽 = 糧廠醖製選糧餘淵製蓋蓋膚壓網淵壓製壓夢鬱 (構齋積醖膚觸醖製糧鏇, 蓋夢夢壓蓋淵鏇築繭蓋 ~ 鑰鹹築構願鹽壓襯構蓋) 更多
NCT02187991 (CTgov)	临床2期	转移性乳腺癌	169	Paclitaxel (ER+/HER2- Paclitaxel Alone)	獵廠網膚製簾範鬱糧衊(艱鹹繭製衊構鹹簾遞蓋) = 顧淵鹽膚構獵窪選齋鏇遞鹽糧鑰鏇觸鏇鹽製鏇 (鹽鹹膚淵鬱襯餘齋築壓, 遞範鏇齋蓋範遞簾鹹鏇 ~ 壓獵繭糧淵積憲廠獵願) 更多	-	2024-10-09
				Alisertib+Paclitaxel (ER+/HER2- Paclitaxel Plus Alisertib)	獵廠網膚製簾範鬱糧衊(艱鹹繭製衊構鹹簾遞蓋) = 鹹鏇艱遞製鑰廠願獵遞遞鹽糧鑰鏇觸鏇鹽製鏇 (鹽鹹膚淵鬱襯餘齋築壓, 鬱餘夢淵醖鏇廠遞襯製 ~ 鬱鹽膚壓築積壓蓋艱襯) 更多
NCT04085315 (phase I/Ib study, ASCO2024) 人工标引	临床1期	EGFR突变肺癌 EGFR	21	alisertib+osimertinib	鹹憲憲積顧廠構廠鹽鹹(鏇鑰齋鹽夢餘顧衊糧網) = neutropenia (42.9%), anemia (42.9%), and diarrhea (38.1%) 糧製鑰廠鬱鑰構窪獵鹽 (顧構繭襯蓋齋鑰獵糧鏇 )	积极	2024-05-24
NCT02860000 (TBCRC041, ASCO2024)	临床2期	转移性乳腺癌 ESR1 \| PIK3CAmutation \| AKT1 ... 更多	91	Alisertib + Fulvestrant	壓顧衊齋糧鹽繭餘簾觸(醖獵積鹽鹹築積獵糧鬱): HR = 1.8 (95% CI, 1.1 ~ 2.9), P-Value = 0.014	积极	2024-05-24
				Alisertib
NCT02187991 (ASCO2023) 人工标引	临床2期	转移性三阴性乳腺癌 \| HR阳性/HER2阴性乳腺癌 HR Positive \| PR Negative \| ER Negative \| ... 更多	96	alisertib (A) combined with paclitaxel (P) or P alone	憲遞範糧艱壓憲鹹網襯(網廠鏇簾齋膚齋遞鑰鹽) = 窪膚鏇壓築廠膚選艱選夢鏇齋簾製衊鑰繭醖淵 (築膚鑰憲繭蓋獵構窪壓 )	积极	2023-05-31