EXPLORE AND TARGET THE EPIGENETIC VULNERABILITY OF PAX3-FOXO1-DRIVEN RHABDOMYOSARCOMA

探索并针对 PAX3-FOXO1 驱动的横纹肌肉瘤的表观遗传脆弱性

基本信息

  • 批准号:
    10521711
  • 负责人:
  • 金额:
    $ 69.14万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2022
  • 资助国家:
    美国
  • 起止时间:
    2022-07-01 至 2027-06-30
  • 项目状态:
    未结题

项目摘要

ABSTRACT The genetic abnormalities that drive tumorigenesis are usually coupled with epigenetic alterations such as aberrant histone lysine methylations due to deregulation of histone methyltransferases and histone lysine demethylases(KDMs). Our long-term goal is to investigate the mechanism by which oncogenic transcription factors “hijack” KDMs in tumorigenesis and disease progression, and develop new therapies to block the functions of these oncoproteins by targeting KDMs. Rhabdomyosarcoma (RMS) is a devastating soft tissue cancer in children and adolescent young adults. The alveolar RMS (aRMS) is a more aggressive subtype, with a higher rate of metastasis. aRMS is primarily driven by the pathognomonic fusion oncoprotein PAX3-FOXO1 or its variant PAX7-FOXO1 through chromosomal translocations of t(2;13)(q35;q14) or t(1;13)(p36;q14). Despite the fact that current treatment modalities have steadily improved survival of low-risk RMS patients, the outcome for the fusion positive aRMS patients with metastasis remains dismal. Even for patients with favorable outcomes, the aggressive chemotherapy and radiotherapy may lead to long-term adverse effects as children may be particularly vulnerable to long-term toxicity. These clinical challenges underscore a pressing need to identify new therapeutic targets and develop better therapies for these patients. However, one obstacle is much less is known about vulnerabilities that arise in transformed cells by PAX3-FOXO1 that could be exploited therapeutically. In this application, we will investigate the functional impact of KDM4 in tumorigenesis driven by PAX3- FOXO1 (Aim 1); dissect the molecular mechanism of KDM4 inhibition on PAX3-FOXO1-driven aRMS (Aim 2), and translate KDM4 inhibitors into novel therapeutic approaches for PAX3-FOXO1 positive aRMS (Aim 3). This innovative study integrates multiple approaches to identify and validate new therapeutic targets and explore small molecules to dually inhibit oncoproteins in the context of a disease that is driven by a undruggable fusion oncoprotein. The proposed research will be impactful for its translational relevance for the treatment of children with high-risk RMS and have the potential to shed new light on the molecular mechanism of PAX3-FOXO1-driven aRMS.
摘要 驱动肿瘤发生的遗传异常通常与表观遗传改变相结合, 由于组蛋白甲基转移酶和组蛋白赖氨酸的失调引起的异常组蛋白赖氨酸甲基化 脱甲基酶(KDM)。我们的长期目标是研究致癌的机制, 转录因子在肿瘤发生和疾病进展中“劫持”KDM,并开发新的治疗方法 通过靶向KDM来阻断这些癌蛋白的功能。横纹肌肉瘤(RMS)是一种 儿童和青少年的毁灭性软组织癌。牙槽骨RMS(aRMS)是一种 侵袭性更强,转移率更高。aRMS主要由特异性 融合癌蛋白PAX 3-FOXO 1或其变体PAX 7-FOXO 1通过染色体易位 t(2;13)(q35;q14)或t(1;13)(p36;q14)。尽管目前的治疗方式已经稳定地 改善低风险RMS患者的生存率,融合阳性aRMS患者的结局 转移仍然令人沮丧。即使对于预后良好的患者,积极的化疗和 放疗可能会导致长期的不良反应,因为儿童可能特别容易受到长期的放射性治疗。 毒性这些临床挑战强调了迫切需要确定新的治疗靶点, 为这些患者开发更好的治疗方法。然而,有一个障碍是鲜为人知的, PAX 3-FOXO 1转化细胞中出现的脆弱性,可以在治疗上加以利用。在 在本申请中,我们将研究KDM 4在PAX 3驱动的肿瘤发生中的功能影响。 F0 X 01(Aim 1);剖析KDM 4抑制PAX 3-F0 X 01驱动的aRMS的分子机制(Aim 2),并将KDM 4抑制剂转化为PAX 3-FOXO 1阳性aRMS的新治疗方法(Aim 3)。这项创新的研究整合了多种方法来识别和验证新的治疗靶点 并探索小分子在疾病的背景下双重抑制癌蛋白, 非药物性融合癌蛋白。拟议的研究将因其翻译相关性而产生影响, 治疗儿童高危RMS,并有可能揭示新的分子 PAX 3-FOXO 1驱动的aRMS的机制。

项目成果

期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

数据更新时间:{{ journalArticles.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ monograph.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ sciAawards.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ conferencePapers.updateTime }}

{{ item.title }}
  • 作者:
    {{ item.author }}

数据更新时间:{{ patent.updateTime }}

Xiang Chen其他文献

Xiang Chen的其他文献

{{ item.title }}
{{ item.translation_title }}
  • DOI:
    {{ item.doi }}
  • 发表时间:
    {{ item.publish_year }}
  • 期刊:
  • 影响因子:
    {{ item.factor }}
  • 作者:
    {{ item.authors }}
  • 通讯作者:
    {{ item.author }}

{{ truncateString('Xiang Chen', 18)}}的其他基金

EXPLORE AND TARGET THE EPIGENETIC VULNERABILITY OF PAX3-FOXO1-DRIVEN RHABDOMYOSARCOMA
探索并针对 PAX3-FOXO1 驱动的横纹肌肉瘤的表观遗传脆弱性
  • 批准号:
    10649516
  • 财政年份:
    2022
  • 资助金额:
    $ 69.14万
  • 项目类别:
The Role of Immature Tumor Subpopulations In Pediatric Rhabdomyosarcoma
未成熟肿瘤亚群在小儿横纹肌肉瘤中的作用
  • 批准号:
    10584592
  • 财政年份:
    2022
  • 资助金额:
    $ 69.14万
  • 项目类别:
The Role of Immature Tumor Subpopulations In Pediatric Rhabdomyosarcoma
未成熟肿瘤亚群在小儿横纹肌肉瘤中的作用
  • 批准号:
    10445963
  • 财政年份:
    2022
  • 资助金额:
    $ 69.14万
  • 项目类别:

相似海外基金

Exploring the mental health and wellbeing of adolescent parent families affected by HIV in South Africa
探讨南非受艾滋病毒影响的青少年父母家庭的心理健康和福祉
  • 批准号:
    ES/Y00860X/1
  • 财政年份:
    2024
  • 资助金额:
    $ 69.14万
  • 项目类别:
    Fellowship
Scaling-up co-designed adolescent mental health interventions
扩大共同设计的青少年心理健康干预措施
  • 批准号:
    MR/Y020286/1
  • 财政年份:
    2024
  • 资助金额:
    $ 69.14万
  • 项目类别:
    Fellowship
Shared Spaces: The How, When, and Why of Adolescent Intergroup Interactions
共享空间:青少年群体间互动的方式、时间和原因
  • 批准号:
    ES/T014709/2
  • 财政年份:
    2024
  • 资助金额:
    $ 69.14万
  • 项目类别:
    Research Grant
Social Media Mechanisms Affecting Adolescent Mental Health (SoMe3)
影响青少年心理健康的社交媒体机制 (SoMe3)
  • 批准号:
    MR/X034925/1
  • 财政年份:
    2024
  • 资助金额:
    $ 69.14万
  • 项目类别:
    Fellowship
Parent-adolescent informant discrepancies: Predicting suicide risk and treatment outcomes
父母与青少年信息差异:预测自杀风险和治疗结果
  • 批准号:
    10751263
  • 财政年份:
    2024
  • 资助金额:
    $ 69.14万
  • 项目类别:
Adolescent sugar overconsumption programs food choices via altered dopamine signalling
青少年糖过度消费通过改变多巴胺信号来影响食物选择
  • 批准号:
    BB/Y006496/1
  • 财政年份:
    2024
  • 资助金额:
    $ 69.14万
  • 项目类别:
    Research Grant
The Impact of Online Social Interactions on Adolescent Cognition
在线社交互动对青少年认知的影响
  • 批准号:
    DE240101039
  • 财政年份:
    2024
  • 资助金额:
    $ 69.14万
  • 项目类别:
    Discovery Early Career Researcher Award
Resilience Factors, Pain, and Physical Activity in Adolescent Chronic Musculoskeletal Pain
青少年慢性肌肉骨骼疼痛的弹性因素、疼痛和体力活动
  • 批准号:
    10984668
  • 财政年份:
    2024
  • 资助金额:
    $ 69.14万
  • 项目类别:
Augmented Social Play (ASP): smartphone-enabled group psychotherapeutic interventions that boost adolescent mental health by supporting real-world connection and sense of belonging
增强社交游戏 (ASP):智能手机支持的团体心理治疗干预措施,通过支持现实世界的联系和归属感来促进青少年心理健康
  • 批准号:
    10077933
  • 财政年份:
    2023
  • 资助金额:
    $ 69.14万
  • 项目类别:
    EU-Funded
Family-Focused Adolescent & Lifelong Health Promotion (FLOURISH)
以家庭为中心的青少年
  • 批准号:
    10050850
  • 财政年份:
    2023
  • 资助金额:
    $ 69.14万
  • 项目类别:
    EU-Funded
{{ showInfoDetail.title }}

作者:{{ showInfoDetail.author }}

知道了