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

基本信息

  • 批准号:
    10584592
  • 负责人:
  • 金额:
    $ 40.8万
  • 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:
    2022-03-04 至 2027-02-28
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY / ABSTRACT Rhabdomyosarcoma (RMS) is a devastating pediatric soft tissue cancer with morphological features of develop- ing skeletal muscles. Although most patients with RMS achieve a complete remission, one third will develop disease recurrence which is associated with a dismal clinical outcome. These clinical challenges underscore an urgent need to identify patients at risk for resistance and develop better therapy to reduce the risk of recurrence. Our pilot study revealed that rhabdomyosarcoma tumors have developmental intratumoral heterogeneity: differ- ent cells in a single tumor harbor transcriptomic feature of different myogenic stages. Moreover, tumor cells with developmentally immature characteristics are enriched in post-therapy specimens and have the potential to rep- licate and reconstitute the entire developmental trajectory after therapy. In this application, we will develop com- putational analysis methods to unambiguously identify immature tumor subpopulations in single cell RNA-seq data and to reveal their master deregulated genes (Aim 1); In Aim 2, we will characterize the changes in those transcriptional networks and cellular states during treatment in orthoptic patient derived xenograft models (O- PDXs) in vivo. And in Aim 3, we will develop an innovative deep-learning data mining approach to evaluate the prognostic significance of the myogenic transcriptional networks that underly RMS cellular heterogeneity in pa- tient tumors. The proposed study integrates computational, statistical and experimental approaches to study the role of immature cell populations in rhabdomyosarcoma recurrence. Building upon our computational expertise, research experience in rhabdomyosarcoma, robust preliminary results and highly productive collaborations with multi-disciplinary expertise in genomics/epigenomics, machine learning, Bayesian statistics and translational re- search in rhabdomyosarcoma, we are in a unique position to achieve the goals of this research proposal. The proposed research will be impactful because it will potentially change how we treat children with rhabdomyosar- coma and the developed computational/statistical approaches will be broadly applicable to cancer research.
项目总结/摘要 横纹肌肉瘤(RMS)是一种破坏性的儿童软组织癌,具有发育不全的形态学特征。 骨骼肌虽然大多数RMS患者达到完全缓解,但仍有三分之一的患者会发展为 疾病复发,其与令人沮丧的临床结果相关。这些临床挑战强调了 迫切需要识别耐药风险患者,并开发更好的治疗方法以降低复发风险。 我们的初步研究显示横纹肌肉瘤肿瘤具有发展的瘤内异质性:不同的肿瘤细胞, 单个肿瘤中的ENT细胞具有不同肌源性阶段的转录组学特征。此外,具有 发育不成熟的特征在治疗后的标本中富集,并有可能复制。 在治疗后描绘并重建整个发展轨迹。在这个应用程序中,我们将开发COM- 在单细胞RNA-seq中明确鉴定未成熟肿瘤亚群的推定分析方法 数据,并揭示他们的主失调基因(目标1);在目标2中,我们将描述这些变化的特点, 在直视患者来源的异种移植物模型(O-100)中治疗期间的转录网络和细胞状态 PDX)。在目标3中,我们将开发一种创新的深度学习数据挖掘方法来评估 肌源性转录网络的预后意义,该网络是帕金森病RMS细胞异质性的基础。 恶性肿瘤该研究综合了计算、统计和实验方法, 未成熟细胞群在横纹肌肉瘤复发中的作用基于我们的计算专业知识, 横纹肌肉瘤的研究经验,稳健的初步结果和与 在基因组学/表观基因组学、机器学习、贝叶斯统计和翻译重 在横纹肌肉瘤的研究中,我们处于一个独特的位置来实现这项研究建议的目标。的 拟议的研究将是有影响力的,因为它可能会改变我们治疗横纹肌肉瘤儿童的方式, COMA和所开发的计算/统计方法将广泛适用于癌症研究。

项目成果

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Xiang Chen其他文献

Xiang Chen的其他文献

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{{ 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:
    10521711
  • 财政年份:
    2022
  • 资助金额:
    $ 40.8万
  • 项目类别:
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:
    $ 40.8万
  • 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:
    $ 40.8万
  • 项目类别:

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