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

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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