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A review calling for research directed at early detection of childhood cancers: The clinical, scientific, and economic arguments for population screening and surveillance 呼吁开展儿童癌症早期检测研究的综述:人群筛查和监测的临床、科学和经济论据
Pub Date : 2024-09-26 DOI: 10.1016/j.ejcped.2024.100191
Childhood cancers are increasingly recognised as disorders of tissue growth and development, through early life into adulthood. A rising proportion are currently considered to be related to a familial predisposition or associated with identified genetic mutations in predisposition genes. Their threat to life and risk of associated serious disability at diagnosis and need for complex life saving therapies makes them a research priority. Inadequate progress has been made in diagnosing childhood cancers earlier within global health systems, which means that their clinical presentations are either missed altogether or constitute high risk emergencies. Whilst knowledge of tumour biology has improved dramatically over the last decade due to the expansion in research technologies directed at innovative approaches to prognostication and treatment. A concerted research initiative to apply this knowledge to making the diagnosis of childhood cancers at earlier points in tumourgenesis has not developed. The risk for a child getting a cancer by the age of 5 is equivalent to the risks of the conditions selected as part of newborn population screening for rare inherited health conditions and is nearly 3 times that at age 18 years. We are proposing that research directed at accelerating cancer diagnosis for children by focussing upon feasibility and acceptability of linking targeted surveillance with population screening for all childhood cancers. This would be supported by enhanced public and professional awareness of a child’s risks of cancer and the range of clinical presentations. We suggest this must now be a top priority for research because of the potential for improving outcomes for treatment of all types of cancer and reducing the burden of disability and late effects of therapy.
越来越多的人认识到,儿童癌症是一种从生命早期到成年期的组织生长和发育障碍。目前,越来越多的儿童癌症被认为与家族遗传倾向有关,或与已发现的易感基因突变有关。这些疾病对生命构成威胁,确诊时有可能导致严重残疾,需要复杂的救生疗法,因此成为研究的重点。全球卫生系统在早期诊断儿童癌症方面进展不足,这意味着这些癌症的临床表现要么被完全遗漏,要么构成高风险急症。过去十年来,由于针对预后和治疗创新方法的研究技术不断扩展,人们对肿瘤生物学的认识有了显著提高。但是,将这些知识应用于在肿瘤发生的早期阶段对儿童癌症进行诊断的协调一致的研究计划还没有发展起来。儿童在 5 岁前罹患癌症的风险与新生儿罕见遗传性疾病筛查所选疾病的风险相当,是 18 岁时的近 3 倍。我们建议开展旨在加快儿童癌症诊断的研究,重点关注将目标监测与所有儿童癌症的人群筛查联系起来的可行性和可接受性。这将得到公众和专业人士对儿童患癌风险和各种临床表现的进一步认识的支持。我们建议现在必须将此作为研究的重中之重,因为这有可能改善所有类型癌症的治疗效果,减轻残疾负担和治疗的后期影响。
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引用次数: 0
Intermittent micafungin dosing schedule in pediatric oncology patients ‐ safe for outpatient parenteral antimicrobial therapy? 儿科肿瘤患者的间歇性米卡芬净用药计划--门诊肠外抗菌治疗安全吗?
Pub Date : 2024-09-08 DOI: 10.1016/j.ejcped.2024.100189

Introduction

Antifungal prophylaxis is an important preventative strategy for high-risk pediatric oncology patients. When triazoles are contraindicated, micafungin is an alternative to polyenes, due to improved tolerability and limited drug-drug interactions. An intermittent dosing schedule is advantageous for outpatient parenteral antimicrobial therapy (OPAT), but studies assessing safety in pediatric patients are limited.

Methods

This single-centre, retrospective, observational study compared the safety and tolerability of daily (1 mg/kg) and intermittent (3 mg/kg) dosing of amphotericin B liposomal (AmB) and micafungin in children under 18 years, with high-risk leukemia. Results
Of 51 patients, with 76 individual dosing schedules, hepatoxicity and nephrotoxicity were comparable across all four dosing schedules. Severity of hypokalemia was significantly higher amongst patients receiving AmB (p = 0.041), with higher rates of intravenous electrolyte supplementation required. Infusion-related reactions occurred only in the AmB group (22 %). Intermittent administration and dosing of micafungin was well tolerated, with similar effects on liver function and reduced rates of hypokalemia.

Conclusion

This study supports the positive safety profile of intermittent micafungin compared with AmB and describes successful OPAT implementation. Prospective studies assessing efficacy are needed to validate these findings.
导言抗真菌预防是儿科肿瘤高危患者的重要预防策略。在禁用三唑类药物的情况下,米卡芬净因其更好的耐受性和有限的药物相互作用,成为多烯类药物的替代品。这项单中心、回顾性、观察性研究比较了18岁以下高危白血病患儿每天(1毫克/千克)和间歇(3毫克/千克)服用两性霉素B脂质体(AmB)和米卡芬净的安全性和耐受性。结果 在 51 名患者的 76 种给药方案中,四种给药方案的肝毒性和肾毒性相当。接受氨溴索治疗的患者低钾血症的严重程度明显更高(p = 0.041),需要静脉补充电解质的比例也更高。输液相关反应仅发生在 AmB 组(22%)。间歇性给药和给药米卡芬净的耐受性良好,对肝功能的影响相似,低钾血症发生率降低。需要对疗效进行前瞻性研究来验证这些发现。
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引用次数: 0
Approved medicines for paediatric solid tumours in Europe: Lessons from the life cycle of a paediatric investigation plan 欧洲儿科实体瘤获批药物:儿科调查计划生命周期的经验教训
Pub Date : 2024-09-08 DOI: 10.1016/j.ejcped.2024.100190

Background

Despite the positive changes brought by the Paediatric Regulation in the European Union (EU) in 2007, drug development in children remains challenging.

Methods

To better understand the issues encountered to reach an authorisation for paediatric patients, we reviewed the pathway of the 11 Paediatric Investigational Plans (PIPs) with indications targeting paediatric solid tumours granted by the Committee for Medicinal Products for Human Use (CHMP) between 2007 and 2022.

Results

On average 5,5 years were necessary to reach approval after a PIP was agreed. All the PIPs underwent at least one modification (median 3 modifications per PIP). The use of single arm trials, in the context of refractory/relapsed disease in absence of standard of care treatment, was supportive for granting a paediatric indication in the majority of the cases. In 6 out of 11 approved products, extrapolation from adults was used. For 2/11 the approval focused on an older population first compared to the initial age group agreed in the PIP due to the development of a suitable formulation for younger children still ongoing at the time of first approval. Scientific advice sought on paediatric development use of extrapolation from adults, major objections raised by CHMP and post-marketing requirements were examined.

Conclusion

Analysing the process necessary to reach an authorisation for paediatric patients, we highlight the major challenges faced in the paediatric approval process and the positive examples of successful drug development that reached final approval. Our analysis is expected to provide useful insights to drug developers, investigators and regulators.

背景尽管 2007 年欧盟(EU)的儿科法规带来了积极的变化,但儿童药物的开发仍然充满挑战。方法为了更好地了解儿科患者获得授权所遇到的问题,我们回顾了 2007 年至 2022 年间人用药产品委员会(CHMP)批准的 11 个适应症为儿科实体瘤的儿科研究计划(PIP)的路径。所有 PIP 至少经过一次修改(每个 PIP 的修改次数中位数为 3 次)。在没有标准疗法的情况下,对难治性/复发性疾病进行单臂试验,在大多数情况下都有助于批准儿科适应症。在 11 个获批产品中,有 6 个采用了成人外推法。其中 2/11 个产品的批准首先针对的是年龄较大的人群,而不是 PIP 中最初商定的年龄组,原因是在首次批准时,针对年龄较小儿童的合适制剂的开发工作仍在进行中。结论通过分析儿科患者获得授权的必要过程,我们强调了儿科审批过程中面临的主要挑战,以及获得最终批准的成功药物开发的正面例子。我们的分析有望为药物开发人员、研究人员和监管人员提供有益的启示。
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引用次数: 0
Common core variables for childhood cancer data integration 儿童癌症数据整合的共同核心变量
Pub Date : 2024-08-31 DOI: 10.1016/j.ejcped.2024.100186

Introduction

Data-driven research has improved paediatric cancer outcomes for children. However, challenges in sharing data between institutions prevent the use of artificial intelligence (AI) to address substantial unmet needs in children diagnosed with cancer. Harmonising collected data can enable the application of AI for a greater understanding of paediatric cancers. The main goal of the paper was to analyse the currently used childhood cancer databases to identify a core of variables able to capture the most relevant data on the diagnosis and treatment of children and adolescents with cancer.

Methods

We arbitrarily identified different types of existing databases dedicated to collecting data of patients with solid tumours, Umbrella, FAR-RMS; PARTNER; ERN PAEDCAN Registry; INSTRUCT and INRG; the common data elements for Rare Disease by Joint Research Centre. The different elements of the CRFs were analysed and ranked “essential” and “good to have”. Domains that included a group of variables structurally connected were identified. Each variable was defined by name, data type, description, and permissible values.

Results

We identified six structural domains: Patient registration, Personal information, Disease History, Diagnosis, Treatment, and Follow-up and Events. For each of them, “essential” and “good to have” variables were defined.

Discussion

Data harmonisation is essential for enhancing integration and comparability in research. By standardizing data formats and variables, researchers can facilitate data sharing, collaboration, and analysis across multiple studies and datasets. Embracing data harmonization practices will advance application of AI, scientific knowledge, improve research reproducibility, and contribute to evidence-based decision-making in various fields.

导言:数据驱动的研究改善了儿童癌症的治疗效果。然而,机构间共享数据方面的挑战阻碍了人工智能(AI)的应用,无法满足确诊癌症儿童的大量需求。统一所收集的数据可以使人工智能的应用更深入地了解儿科癌症。本文的主要目的是分析目前使用的儿童癌症数据库,以确定能够捕捉儿童和青少年癌症患者诊断和治疗最相关数据的核心变量。方法我们任意确定了现有的专门收集实体瘤患者数据的不同类型数据库:Umbrella、FAR-RMS、PARTNER、ERN PAEDCAN Registry、INSTRUCT 和 INRG;以及联合研究中心的罕见病通用数据元素。对通用报告格式的不同要素进行了分析,并将其分为 "必需 "和 "适合 "两个等级。确定了包含一组结构相连变量的领域。每个变量的定义包括名称、数据类型、描述和允许值:我们确定了六个结构域:患者登记、个人信息、病史、诊断、治疗以及随访和事件。讨论数据协调对于提高研究的整合性和可比性至关重要。通过标准化数据格式和变量,研究人员可以促进多项研究和数据集之间的数据共享、协作和分析。采用数据统一做法将推动人工智能和科学知识的应用,提高研究的可重复性,并有助于各领域的循证决策。
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引用次数: 0
Cross-border access to early phase clinical trials for children with cancer in the Nordic region 北欧地区儿童癌症早期临床试验的跨境准入问题
Pub Date : 2024-08-30 DOI: 10.1016/j.ejcped.2024.100188

Introduction

As 15 % of childhood cancers are still incurable, early phase clinical trials are essential in developing better therapies for children with cancer. Accessing relevant trials can be challenging, exacerbated by increasingly specialized therapies which are not available in every country. Copenhagen houses the main early phase trial center for children with cancer in the Nordic region, with about half of trial participants coming from abroad. We explored factors facilitating cross-border access to early phase pediatric cancer trials in Copenhagen.

Methods and materials

Interviews were conducted with 11 family members from five families and nineteen healthcare providers on socio-cultural aspects of traveling for the trial. A thematic analysis was conducted.

Results

Three major themes were identified: proximity to a trial center, facilitation of referral and logistics, and families’ and providers’ perceptions. Both geographic proximity and socio-cultural proximity facilitated access. Provider networks facilitated referrals and sponsors paid for travel, improving feasibility for families. Finally, families’ feelings of hope and providers’ positive perceptions of experimental therapy also promoted access to early phase trials.

Conclusions

Our findings highlight the importance of fully supporting families through logistics, expenses, and challenges associated with traveling to a clinical trial, the value of robust provider networks in facilitating referrals, and the need for awareness of potential socio-cultural bias in referring patients. While factors like geography and attitude also mitigate access, many barriers can be overcome by comprehensive support for families, improving access to early phase trials for children with cancer.

导言:目前仍有 15% 的儿童癌症无法治愈,因此早期临床试验对于开发更好的儿童癌症疗法至关重要。但要获得相关试验的机会却很困难,而越来越多的专业治疗方法并非在每个国家都能获得,这就更加剧了这一问题。哥本哈根是北欧地区主要的儿童癌症早期试验中心,约有一半的试验参与者来自国外。我们探讨了促进跨境参加哥本哈根儿童癌症早期试验的因素。方法和材料我们对来自五个家庭的 11 名家庭成员和 19 名医疗服务提供者进行了访谈,内容涉及旅行参加试验的社会文化方面。结果确定了三大主题:与试验中心的距离、转诊和物流的便利性以及家庭和医疗服务提供者的看法。地理位置的接近和社会文化的接近都为获得试验提供了便利。服务提供者网络为转介提供了便利,赞助商支付了旅费,提高了家庭的可行性。最后,家庭的希望感和医疗服务提供者对试验疗法的积极看法也促进了早期阶段试验的获得。结论我们的研究结果强调了全力支持家庭克服与前往临床试验相关的后勤、费用和挑战的重要性,强大的医疗服务提供者网络在促进转诊方面的价值,以及在转诊患者时需要意识到潜在的社会文化偏见。虽然地理位置和态度等因素也会影响临床试验的获得,但通过为家庭提供全面支持,可以克服许多障碍,从而提高儿童癌症患者获得早期临床试验的机会。
{"title":"Cross-border access to early phase clinical trials for children with cancer in the Nordic region","authors":"","doi":"10.1016/j.ejcped.2024.100188","DOIUrl":"10.1016/j.ejcped.2024.100188","url":null,"abstract":"<div><h3>Introduction</h3><p>As 15 % of childhood cancers are still incurable, early phase clinical trials are essential in developing better therapies for children with cancer. Accessing relevant trials can be challenging, exacerbated by increasingly specialized therapies which are not available in every country. Copenhagen houses the main early phase trial center for children with cancer in the Nordic region, with about half of trial participants coming from abroad. We explored factors facilitating cross-border access to early phase pediatric cancer trials in Copenhagen.</p></div><div><h3>Methods and materials</h3><p>Interviews were conducted with 11 family members from five families and nineteen healthcare providers on socio-cultural aspects of traveling for the trial. A thematic analysis was conducted.</p></div><div><h3>Results</h3><p>Three major themes were identified: proximity to a trial center, facilitation of referral and logistics, and families’ and providers’ perceptions. Both geographic proximity and socio-cultural proximity facilitated access. Provider networks facilitated referrals and sponsors paid for travel, improving feasibility for families. Finally, families’ feelings of hope and providers’ positive perceptions of experimental therapy also promoted access to early phase trials.</p></div><div><h3>Conclusions</h3><p>Our findings highlight the importance of fully supporting families through logistics, expenses, and challenges associated with traveling to a clinical trial, the value of robust provider networks in facilitating referrals, and the need for awareness of potential socio-cultural bias in referring patients. While factors like geography and attitude also mitigate access, many barriers can be overcome by comprehensive support for families, improving access to early phase trials for children with cancer.</p></div>","PeriodicalId":94314,"journal":{"name":"EJC paediatric oncology","volume":null,"pages":null},"PeriodicalIF":0.0,"publicationDate":"2024-08-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.sciencedirect.com/science/article/pii/S2772610X24000485/pdfft?md5=0db74d469eefaf7248a98a97b92e4013&pid=1-s2.0-S2772610X24000485-main.pdf","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142136387","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
引用次数: 0
Clinical use-cases and implementation guidelines for the development of valuable AI 开发有价值人工智能的临床应用案例和实施指南
Pub Date : 2024-08-29 DOI: 10.1016/j.ejcped.2024.100187
Contributing to UNICA4EU’s vision to upscale and wide-scale the application of AI technology to pediatric cancer care, this paper provides guidelines for the development of an AI-based ecosystem and its potential implementation into clinical practice. We also provide clinical use cases (UC) that depict scenarios at different stages of the patient journey and showcase how data collected through different methods and techniques interact and could synergize with AI tools to improve diagnosis and risk stratification, facilitate clinical decision making, and help to adequately monitor patients’ quality of life (QoL). Pediatric oncologists and AI specialists crafted each UC considering current standards, unmet needs, and advancements in both precision medicine and AI to address identified challenges. UC depict transferable methods and processes applicable to other diseases, and show how different techniques could ideally converge at different stages, representing a use case on its own.
UNICA4EU 的愿景是提升和扩大人工智能技术在儿科癌症护理中的应用,本文为开发基于人工智能的生态系统及其在临床实践中的潜在应用提供了指导。我们还提供了临床用例 (UC),描述了患者治疗过程中不同阶段的场景,展示了通过不同方法和技术收集的数据如何与人工智能工具相互作用、协同增效,以改善诊断和风险分层,促进临床决策,并帮助充分监控患者的生活质量 (QoL)。儿科肿瘤专家和人工智能专家在制定每项 UC 时,都会考虑到当前的标准、未满足的需求以及精准医疗和人工智能的进步,以应对已确定的挑战。UC 描述了适用于其他疾病的可转移方法和流程,并展示了不同技术如何在不同阶段理想地融合,这本身就是一个用例。
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引用次数: 0
Multimodality imaging of bone marrow involvement in paediatric oncology 儿科肿瘤学中骨髓受累的多模式成像
Pub Date : 2024-08-13 DOI: 10.1016/j.ejcped.2024.100185

Identifying bone marrow involvement (with or without bone destruction) in children with cancer is essential for adequate diagnosis, prognostication, therapy planning, and response assessment. Imaging plays an increasing role, with MRI including DWI and [18F]FDG-PET/CT as the most commonly used imaging techniques. Interpretation of the paediatric bone marrow on imaging might be challenging because of age-related physiological changes in the bone marrow, as well as disease and therapy related effects. In this review, we discuss how the imaging techniques available may be employed to detect bone marrow involvement (BMI) in paediatric oncology. Furthermore, insights into physiological, disease and therapy related bone marrow changes in children that might influence bone marrow imaging interpretation will be provided.

确定癌症患儿的骨髓受累情况(有无骨质破坏)对于充分诊断、预后判断、治疗计划和反应评估至关重要。成像技术的作用越来越大,最常用的成像技术是核磁共振成像(包括 DWI)和[18F]FDG-PET/CT。由于骨髓与年龄相关的生理变化以及疾病和治疗相关的影响,对儿科骨髓成像的解读可能具有挑战性。在本综述中,我们将讨论如何利用现有的成像技术检测儿科肿瘤中的骨髓受累情况(BMI)。此外,我们还将深入探讨可能影响骨髓成像解读的儿童骨髓生理、疾病和治疗相关变化。
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引用次数: 0
Cell state plasticity in neuroblastoma 神经母细胞瘤的细胞状态可塑性
Pub Date : 2024-08-02 DOI: 10.1016/j.ejcped.2024.100184

Evolving evidence indicates that tumor cells can transdifferentiate between distinct transcriptionally-determined cell states with changes in resultant phenotypes, a phenomenon known as cellular plasticity. These transitions are not driven by genetic mutations and typically in contrast to normal developmental processes, may proceed bidirectionally. Here, we review the role of cellular plasticity in the aggressive childhood solid tumor, neuroblastoma. We discuss the detection of two cell states, termed mesenchymal (MES) and adrenergic (ADRN), their properties and the transcriptional circuitries that control them, their relation to the normal embryogenesis of the sympathetic nervous system and their potential role in drug resistance, escape from therapy and development of relapse.

越来越多的证据表明,肿瘤细胞可以在不同的转录决定的细胞状态之间发生转分化,从而导致表型的改变,这种现象被称为细胞可塑性。这些转变不是由基因突变驱动的,而且与正常的发育过程不同,它们可能是双向的。在此,我们回顾了细胞可塑性在侵袭性儿童实体瘤--神经母细胞瘤中的作用。我们将讨论两种细胞状态(间质细胞(MES)和肾上腺素能细胞(ADRN))的检测、它们的特性和控制它们的转录回路、它们与交感神经系统正常胚胎发育的关系以及它们在耐药性、逃避治疗和复发中的潜在作用。
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引用次数: 0
Re-irradiation for progressive Diffuse Intrinsic Pontine Glioma (DIPG): The Spanish experience 对进展期弥漫性桥脑胶质瘤(DIPG)进行再放射治疗:西班牙的经验
Pub Date : 2024-07-30 DOI: 10.1016/j.ejcped.2024.100183

Introduction

Diffuse intrinsic pontine glioma (DIPG) is the most common malignant brainstem tumour in children. Despite advances in understanding its biology, current treatments have shown minimal impact on overall survival in this fatal disease. Focal radiotherapy (RT) is the only treatment proven to improve symptoms and extend progression-free survival. Albeit palliative, re-irradiation (rRT) has emerged as the best alternative for progressive disease. This study presents the Spanish experience with re-irradiation in DIPG.

Results

Between April 2015 and December 2023, 44 paediatric patients with progressive DIPG underwent rRT in 16 Spanish institutions. Median time from diagnosis to progression was 9.9 months (range, 4.2–24.3 months). Median dose of rRT was 20 Gy (range, 18–40 Gy) in 2 Gy fractions (range, 1.3–4 Gy). Twenty-two patients (50 %) received other treatments besides RT. Clinical improvement was seen in 77.3 %, and radiological improvement in 60 %. Treatment was well tolerated (1 case toxicity >grade 2 related to rRT). Median overall survival was 15.5 months (range, 8.2–63.2 months), with a median time from rRT to death of 4.2 months (range, 0.6–10.3 months). Longer time between diagnosis and rRT (>10 months) and dose of rRT >20 Gy were statistically significantly correlated with better overall survival. There was no survival benefit in patients receiving additional treatments.

Conclusions

Re-irradiation is safe and effective in progressive DIPG patients, not only improving symptoms but also prolonging survival. However, the ideal candidates for rRT remain undefined, as well as the best irradiation scheme. Prospective studies are needed.

导言弥漫性桥脑胶质瘤(DIPG)是儿童最常见的脑干恶性肿瘤。尽管对其生物学特性的了解取得了进展,但目前的治疗方法对这种致命疾病的总体生存率影响甚微。局部放射治疗(RT)是唯一被证明能改善症状和延长无进展生存期的治疗方法。尽管是姑息性治疗,但再照射(rRT)已成为治疗进展性疾病的最佳选择。结果2015年4月至2023年12月期间,西班牙16家医疗机构共对44名进展期DIPG儿科患者进行了再照射治疗。从诊断到病情进展的中位时间为9.9个月(范围为4.2-24.3个月)。rRT的中位剂量为20 Gy(范围为18-40 Gy),分次剂量为2 Gy(范围为1.3-4 Gy)。22名患者(50%)接受了 RT 以外的其他治疗。77.3%的患者临床症状有所改善,60%的患者放射学症状有所改善。治疗耐受性良好(1例2级毒性反应与RRT有关)。中位总生存期为15.5个月(范围为8.2-63.2个月),从接受放射治疗到死亡的中位时间为4.2个月(范围为0.6-10.3个月)。从诊断到接受放射治疗的时间越长(10个月),接受放射治疗的剂量越大(20Gy),总生存率就越高。结论再照射对进展期DIPG患者安全有效,不仅能改善症状,还能延长生存期。结论再照射对进展期DIPG患者安全有效,不仅能改善症状,还能延长生存期。然而,再照射治疗的理想人选和最佳照射方案仍未确定。需要进行前瞻性研究。
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引用次数: 0
MYCN in neuroblastoma: The kings' new clothes and drugs 神经母细胞瘤中的 MYCN:国王的新衣和药物
Pub Date : 2024-07-27 DOI: 10.1016/j.ejcped.2024.100182

Deregulated levels of the MYCN oncogene contribute to the tumorigenesis of several human tumors including neuroblastoma. MYCN amplification classifies neuroendocrine tumors as high-risk and as a consequence is an unfavorable prognostic factor. MYCN has long been primarily described as a transcription factor, which binds to active promoters after heterodimerizing with MAX and directly regulates gene expression programs. New findings show that MYC proteins have novel oncogenic functions that are tumor-promoting and go beyond the regulation of gene expression. This review describes how MYCN continuously drives tumor progression by forming various protein complexes, for example to resolve torsional stress, coordinate transcription and replication, repair DNA damage and regulate R-loops. Interfering with the described processes as well as interfering with MYCN chromatin binding emerge as novel treatment strategies to indirectly target the oncoprotein. Furthermore, we describe the role of MYCN in metabolism and we review how these newly described functions of MYCN could be used as vulnerabilities for MYCN-driven tumors. Recent studies show that MYC proteins are capable of multimerizing at sites of genomic instability to protect cancer cells from stress. Additionally, MYCN can bind aberrant RNA transcripts, another feature to enhance the stress resilience of cancer cells, once again highlighting the oncogenic potential of MYC. Taken together, we show that the diverse functions of MYCN depend on its temporal and spatial dynamic interactome, making those interaction partners and functions crucial factors in the treatment of MYCN-related cancer.

MYCN 致癌基因水平失调是包括神经母细胞瘤在内的多种人类肿瘤发生的原因之一。MYCN 扩增将神经内分泌肿瘤归为高危肿瘤,因此是一个不利的预后因素。长期以来,MYCN 主要被描述为一种转录因子,它与 MAX 异源二聚体后与活跃的启动子结合,直接调控基因表达程序。新的研究结果表明,MYC 蛋白具有新的致癌功能,不仅能调节基因表达,还能促进肿瘤生长。本综述介绍了 MYCN 如何通过形成各种蛋白质复合物,例如解决扭转应力、协调转录和复制、修复 DNA 损伤和调节 R 环,不断推动肿瘤的发展。干扰所述过程以及干扰 MYCN 染色质结合成为间接针对该肿瘤蛋白的新型治疗策略。此外,我们还描述了 MYCN 在新陈代谢中的作用,并回顾了如何利用这些新描述的 MYCN 功能作为 MYCN 驱动的肿瘤的弱点。最近的研究表明,MYC 蛋白能够在基因组不稳定的位点多聚化,以保护癌细胞免受压力。此外,MYCN 还能结合异常 RNA 转录本,这是增强癌细胞抗应激能力的另一个特征,再次凸显了 MYC 的致癌潜力。综上所述,我们发现 MYCN 的多种功能取决于其时空动态相互作用组,因此这些相互作用伙伴和功能成为治疗 MYCN 相关癌症的关键因素。
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引用次数: 0
期刊
EJC paediatric oncology
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