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：
10563200
负责人：
Angelina V Vaseva
金额：
$ 34.75万
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/10563200
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 Combination Drug Therapy 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 PIK3CG gene Pathway interactions Patients Pharmaceutical Preparations Pharmacodynamics Pilot Projects Protein Isoforms Proto-Oncogene Proteins c-akt Protocols documentation Radiation therapy Recurrence Regimen Regulation Resistance Rhabdomyosarcoma Role Schedule Signal Transduction Testing Therapeutic Toxic effect Translations Vincristine Xenograft Model Xenograft procedure 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 synergism 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，但具有高风险横纹肌肉瘤（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- 在诊断后5年的5年生存率）在过去30年中没有显着改善。此外，当前多模式疗法与终生威胁生命的后遗症有关。这个项目重点开发针对RAS突变剂ERMS的细胞毒性，靶向疗法。初步数据支持快速翻译 MAPK途径作为ERMS的治疗方法的垂直靶向。拟议的目标是基于根据以下观察：（i）在RAS驱动的ERMS中，对MEK抑制剂的抗性是结果通过CRAF重新激活途径；（ii）新一代2型RAF抑制剂与MEK抑制剂的组合引起大多数RAS突变ERMS PDX模型的戏剧性回归，但无法治愈。因此，两者内在的和获得的抵抗力将成为长期治愈结果的障碍；（iii）创新的单鼠测试（SMT）实验设计表明，与它们的高风险分类一致 PDX/CDX模型，最新的高风险RMS临床中使用协议（ARST0431）。因此，该项目的目的是：1）定义先天和获得抵抗的机制在RAS驱动的ERMS中共同推动RAF和MEK，以促进更具影响力的临床结果。使用DNA和RNA测序，我们将确定与抗药性和验证和定义与先天和获得2型RAF和MEK抑制剂相结合的抗性的机制在erms中； 2）评估如何使用这种方法将这种方法整合到当前的临床化学疗法方案中 SMT实验设计。我们的研究将为生物标志物提供对2型RAF + MEK抑制剂的反应组合以及如何相对于化学疗法对这种组合进行测序，以优化 RMS PDX/CDX模型，因此直接影响了由RAS驱动的ERMS的临床试验设计。