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: 10446046
• 负责人: Angelina V Vaseva
• 金额: $ 35.46万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-01 至 2027-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10446046
• 关键词: Apoptosis; Biological Assay; Cell Cycle Arrest; Cell Line; Chemotherapy and/or radiation; Chemotherapy-Oncologic Procedure; Child; Classification; Clinical; Clinical Protocols; Clinical Trials; Clinical Trials Design; Clonal Evolution; Codon Nucleotides; Combined Modality Therapy; DNA Damage; DNA Repair; DNA sequencing; Data; Diagnosis; Disease; Dose; Down-Regulation; Embryonal Rhabdomyosarcoma; Event; Experimental Designs; FRAP1 gene; Generations; Genetic; Genomics; Goals; Immunohistochemistry; Intervention; Lesion; Life; MAP Kinase Gene; MAPK Signaling Pathway Pathway; MEK inhibition; MEKs; Mitogen-Activated Protein Kinase Inhibitor; Modeling; Mus; Mutation; NF1 gene; Oncogenic; Operative Surgical Procedures; Outcome; Pathway interactions; Patients; Pharmacodynamics; Pilot Projects; Protein Isoforms; Proto-Oncogene Proteins c-akt; Protocols documentation; Radiation therapy; Recurrence; Regimen; Regulation; Resistance; Rhabdomyosarcoma; Risk; Role; Schedule; Signal Transduction; Testing; Therapeutic; Toxic effect; Translations; Vincristine; Xenograft Model; Xenograft procedure; base; chemoradiation; chemotherapeutic agent; chemotherapy; epigenomics; genetic manipulation; genotoxicity; high risk; improved; improved outcome; in vivo; in vivo Model; inhibitor; innovation; knock-down; mutant; novel; patient derived xenograft model; pre-clinical; preclinical evaluation; protocol development; research clinical testing; resistance mechanism; response; response biomarker; sarcoma; screening; targeted treatment; transcriptome sequencing; treatment response; tumor; tumor xenograft

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， 验证并定义对2型RAF和MEK抑制剂组合的先天性和获得性耐药性的机制 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。