Improving Therapeutic Approaches for RAS-driven Embryonal Rhabdomyosarcoma

改善 RAS 驱动的胚胎性横纹肌肉瘤的治疗方法

基本信息

项目摘要

Summary Despite the use of aggressive chemo-radiation therapy, children with high-risk rhabdomyosarcoma (RMS) including advanced or metastatic embryonal RMS (ERMS) with RAS mutations, have very poor outcomes (20- 30% survival at 5 years from diagnosis) with no significant improvement over the last 30 years. Further, current multimodality therapies are associated with life-long life-threatening sequelae. This project focuses on developing less-genotoxic, targeted therapy for RAS-mutant ERMS. Preliminary data support rapid translation of vertical targeting of the MAPK pathway as a therapeutic approach in ERMS. The proposed aims are based upon the following observations: (i) In RAS-driven ERMS, resistance to MEK inhibitors is a consequence of pathway reactivation through CRAF; (ii) Combination of new generation type 2 RAF inhibitors with MEK inhibitors cause dramatic regressions of most RAS-mutant ERMS PDX models but are not curative. Consequently, both intrinsic and acquired resistance will be a barrier for long-term curative outcomes; (iii) Innovative single mouse testing (SMT) experimental design shows that, consistent with their high-risk classification, RAS-mutant ERMS PDX/CDX models, rapidly fail intensive multidrug regimens used in the most recent high-risk RMS clinical protocol (ARST0431). Therefore, this project aims to: 1) define mechanisms of innate and acquired resistance to co-targeting RAF and MEK in RAS-driven ERMS with the goal to facilitate more impactful clinical outcomes. Using DNA and RNA sequencing, we will identify genomic/epigenomic changes associated with resistance and validate and define mechanisms of innate and acquired resistance to combining type 2 RAF and MEK inhibitors in ERMS; 2) evaluate how this approach can be integrated into current clinical chemotherapy protocols using the SMT experimental design. Our studies will inform biomarkers of response to type 2 RAF + MEK inhibitors combination and how this combination can be sequenced relative to chemotherapy to optimize responses of RMS PDX/CDX models, thus directly impacting clinical trials design for RAS-driven ERMS.
总结 尽管使用积极的化学放射治疗,儿童与高风险横纹肌肉瘤(RMS) 包括RAS突变的晚期或转移性胚胎性RMS(ERMS),预后非常差(20- 诊断后5年生存率为30%),在过去30年中没有显著改善。此外,当前 多模式治疗与终身的危及生命的后遗症有关。该项目的重点是 为RAS突变型ERMS开发遗传毒性较小的靶向治疗。初步数据支持快速翻译 MAPK通路的垂直靶向作为ERMS的治疗方法。拟议的目标是基于 根据以下观察:(i)在RAS驱动的ERMS中,对MEK抑制剂的耐药性是以下因素的结果: (ii)新一代2型RAF抑制剂与MEK抑制剂的组合 导致大多数RAS突变型ERMS PDX模型的显著消退,但不具有治愈性。因此,双方 内在和获得性耐药性将成为长期治疗结果的障碍;(iii)创新的单一小鼠 测试(SMT)实验设计表明,与其高风险分类一致,RAS突变ERMS PDX/CDX模型,在最近的高风险RMS临床试验中使用的强化多药治疗方案迅速失效 方案(ARST 0431)。因此,本项目旨在:1)确定先天和后天抗性的机制 在RAS驱动的ERMS中共同靶向RAF和MEK,旨在促进更有影响力的临床结局。 使用DNA和RNA测序,我们将鉴定与耐药性相关的基因组/表观基因组变化, 验证和定义对2型RAF和MEK抑制剂组合的先天性和获得性抗性的机制 2)评估如何将这种方法整合到当前的临床化疗方案中, SMT实验设计。我们的研究将告知生物标志物对2型RAF + MEK抑制剂的反应 组合以及如何相对于化疗对该组合进行排序以优化化疗的响应。 RMS PDX/CDX模型,从而直接影响RAS驱动ERMS的临床试验设计。

项目成果

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Angelina V Vaseva其他文献

Angelina V Vaseva的其他文献

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{{ truncateString('Angelina V Vaseva', 18)}}的其他基金

Improving Therapeutic Approaches for RAS-driven Embryonal Rhabdomyosarcoma
改善 RAS 驱动的胚胎性横纹肌肉瘤的治疗方法
  • 批准号:
    10563200
  • 财政年份:
    2022
  • 资助金额:
    $ 35.46万
  • 项目类别:

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