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溴结构域和末端外结构域抑制剂-儿童表观遗传修饰药物开发儿科战略论坛共识优先级-ACCELERATE。

Bromodomain and extra-terminal inhibitors-A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children-ACCELERATE.

机构信息

ACCELERATE, Europe.

Dana-Farber Cancer Institute/Harvard Medical School, USA.

出版信息

Eur J Cancer. 2021 Mar;146:115-124. doi: 10.1016/j.ejca.2021.01.018. Epub 2021 Feb 16.


DOI:10.1016/j.ejca.2021.01.018
PMID:33601323
Abstract

Based on biology and pre-clinical data, bromodomain and extra-terminal (BET) inhibitors have at least three potential roles in paediatric malignancies: NUT (nuclear protein in testis) carcinomas, MYC/MYCN-driven cancers and fusion-driven malignancies. However, there are now at least 10 BET inhibitors in development, with a limited relevant paediatric population in which to evaluate these medicinal products. Therefore, a meeting was convened with the specific aim to develop a consensus among relevant biopharmaceutical companies, academic researchers, as well as patient and family advocates, about the development of BET inhibitors, including prioritisation and their specific roles in children. Although BET inhibitors have been in clinical trials in adults since 2012, the first-in-child study (BMS-986158) only opened in 2019. In the future, when there is strong mechanistic rationale or pre-clinical activity of a class of medicinal product in paediatrics, early clinical evaluation with embedded correlative studies of a member of the class should be prioritised and rapidly executed in paediatric populations. There is a strong mechanistic and biological rationale to evaluate BET inhibitors in paediatrics, underpinned by substantial, but not universal, pre-clinical data. However, most pan-BET inhibitors have been challenging to administer in adults, since monotherapy results in only modest anti-tumour activity and provides a narrow therapeutic index due to thrombocytopenia. It was concluded that it is neither scientifically justified nor feasible to undertake simultaneously early clinical trials in paediatrics of all pan-BET inhibitors. However, there is a clinical need for global access to BET inhibitors for patients with NUT carcinoma, a very rare malignancy driven by bromodomain fusions, with proof of concept of clinical benefit in a subset of patients treated with BET inhibitors. Development and regulatory pathway in this indication should include children and adolescents as well as adults. Beyond NUT carcinoma, it was proposed that further clinical development of other pan-BET inhibitors in children should await the results of the first paediatric clinical trial of BMS-986158, unless there is compelling rationale based on the specific agent of interest. BDII-selective inhibitors, central nervous system-penetrant BET inhibitors (e.g. CC-90010), and those dual-targeting BET/p300 bromodomain are of particular interest and warrant further pre-clinical investigation. This meeting emphasised the value of a coordinated and integrated strategy to drug development in paediatric oncology. A multi-stakeholder approach with multiple companies developing a consensus with academic investigators early in the development of a class of compounds, and then engaging regulatory agencies would improve efficiency, productivity, conserve resources and maximise potential benefit for children with cancer.

摘要

基于生物学和临床前数据,溴结构域和末端(BET)抑制剂在儿科恶性肿瘤中至少具有三个潜在作用:NUT(睾丸核蛋白)癌、MYC/MYCN 驱动的癌症和融合驱动的恶性肿瘤。然而,目前正在开发至少 10 种 BET 抑制剂,而在评估这些药物的儿科患者群体中,相关的儿童患者数量有限。因此,召开了一次会议,旨在让相关的生物制药公司、学术研究人员以及患者和家属倡导者就 BET 抑制剂的开发达成共识,包括确定优先级以及它们在儿童中的具体作用。尽管自 2012 年以来,BET 抑制剂已在成人临床试验中进行,但第一项儿童研究(BMS-986158)仅在 2019 年开放。未来,当一类药物在儿科具有强有力的机制依据或临床前活性时,应优先考虑对该类药物的成员进行早期临床评估,并在儿科人群中迅速进行嵌入式相关性研究。在儿科中评估 BET 抑制剂具有强有力的机制和生物学依据,这是基于大量但非普遍的临床前数据。然而,由于单药治疗仅导致适度的抗肿瘤活性,并由于血小板减少症而提供狭窄的治疗指数,因此大多数泛 BET 抑制剂在成人中难以给药。结论是,同时在儿科中对所有泛 BET 抑制剂进行早期临床试验在科学上是没有道理的,也是不可行的。然而,对于患有 NUT 癌的患者,即由溴结构域融合驱动的非常罕见的恶性肿瘤,需要全球获得 BET 抑制剂,并且已经在接受 BET 抑制剂治疗的患者亚组中证明了临床获益,这是有临床需求的。在该适应症中,应包括儿童和青少年以及成人。除了 NUT 癌之外,除非基于特定药物具有令人信服的理由,否则建议在进行 BMS-986158 的第一项儿科临床试验之前,不要在儿童中进一步开展其他泛 BET 抑制剂的临床开发。BDII 选择性抑制剂、穿透中枢神经系统的 BET 抑制剂(例如 CC-90010)以及那些双重靶向 BET/p300 溴结构域的抑制剂特别值得关注,需要进一步进行临床前研究。本次会议强调了在儿科肿瘤学中实施协调和综合药物开发策略的价值。通过多家公司在化合物类别的早期开发中与学术研究人员达成共识,然后与监管机构合作的多利益相关者方法,将提高效率、生产力、节约资源并最大限度地提高癌症患儿的潜在获益。

相似文献

[1]
Bromodomain and extra-terminal inhibitors-A consensus prioritisation after the Paediatric Strategy Forum for medicinal product development of epigenetic modifiers in children-ACCELERATE.

Eur J Cancer. 2021-3

[2]
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Eur J Cancer. 2020-11

[3]
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[4]
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[5]
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[6]
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[7]
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[8]
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[9]
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[10]
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引用本文的文献

[1]
Targeting the MYCN-MDM2 pathways for cancer therapy: Are they druggable?

Genes Dis. 2023-10-27

[2]
Multimodal Therapy Approaches for NUT Carcinoma by Dual Combination of Oncolytic Virus with Small Molecule Inhibitors.

Viruses. 2024-5-14

[3]
Impact of ACCELERATE Paediatric Strategy Forums: a review of the value of multi-stakeholder meetings in oncology drug development.

J Natl Cancer Inst. 2024-2-8

[4]
Nuclear condensates of YAP fusion proteins alter transcription to drive ependymoma tumourigenesis.

Nat Cell Biol. 2023-2

[5]
Bromodomain and Extra-Terminal Protein Inhibitors: Biologic Insights and Therapeutic Potential in Pediatric Brain Tumors.

Pharmaceuticals (Basel). 2022-5-26

[6]
Bromodomain and Extra-Terminal Inhibitor BMS-986158 Reverses Latent HIV-1 Infection In Vitro and Ex Vivo by Increasing CDK9 Phosphorylation and Recruitment.

Pharmaceuticals (Basel). 2022-3-10

[7]
The Current Landscape of Targeted Clinical Trials in Non-WNT/Non-SHH Medulloblastoma.

Cancers (Basel). 2022-1-28

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