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

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
项目类别：
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

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.

概括尽管使用了积极的化学放射治疗，患有高危横纹肌肉瘤（RMS）的儿童包括具有 RAS 突变的晚期或转移性胚胎 RMS (ERMS)，结果非常差 (20- 诊断后 5 年生存率为 30%），在过去 30 年中没有显着改善。此外，当前多学科治疗会导致终生危及生命的后遗症。该项目重点关注为 RAS 突变 ERMS 开发基因毒性较低的靶向疗法。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。拟议的目标基于根据以下观察结果：（i）在 RAS 驱动的 ERMS 中，对 MEK 抑制剂的耐药性是通过 CRAF 途径重新激活； (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 ERMS PDX 模型急剧退化，但没有治愈作用。因此，两者内在和获得性耐药性将成为长期疗效的障碍； (iii) 创新的单鼠标测试 (SMT) 实验设计表明，与高风险分类一致，RAS 突变 ERMS PDX/CDX 模型，在最近的高风险 RMS 临床中使用的强化多药治疗方案很快就会失败协议（ARST0431）。因此，该项目旨在：1）定义先天性和后天性抵抗的机制在 RAS 驱动的 ERMS 中共同靶向 RAF 和 MEK，以促进更具影响力的临床结果。使用 DNA 和 RNA 测序，我们将识别与耐药性和相关性相关的基因组/表观基因组变化。验证并定义对 2 型 RAF 和 MEK 抑制剂联合使用的先天性和获得性耐药机制在企业风险管理系统中； 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这种组合进行排序以优化化疗反应 RMS PDX/CDX 模型，从而直接影响 RAS 驱动的 ERMS 的临床试验设计。