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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.

总结