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SUMOylation disruption is toxic for SS18-SSX-driven synovial sarcoma

SUMO化破坏对 SS18-SSX 驱动的滑膜肉瘤具有毒性

基本信息

批准号：
10736999
负责人：
Anthony Charles Faber
金额：
$ 57.11万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-08-02 至 2028-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736999
关键词：
Age Antineoplastic Agents Automobile Driving Biochemical Biology Categories Cell Culture Techniques Cell Death Cell Line Child Chromatin Remodeling Factor Clinic Clinical Clinical Trials Code Combination Drug Therapy Complex DNA Damage Data Databases Deposition Development Diagnosis Disease Employment Event Funding Gene Fusion Genes Genetic Grant Immunotherapy Light Malignant Neoplasms Mediating Modeling Mus Mutation Neoplasm Metastasis Oncogenic Organoids Pathway interactions Patients Pharmacologic Substance Phosphotransferases Post-Translational Protein Processing Prognosis Proteins Proteome Proteomics Recurrence Refractory Research Design Research Personnel Role SMARCE1 gene Safety Series Small Interfering RNA Soft tissue sarcoma Sumoylation Pathway Survival Rate Systemic Therapy Teenagers Testing Therapeutic Toxic effect Translating Translations addiction chemotherapy clinically actionable combat efficacy testing expectation experimental study in vivo inhibitor innovation insight kinase inhibitor knock-down member mortality mouse model novel novel therapeutic intervention novel therapeutics patient derived xenograft model pharmacologic pre-clinical preclinical study restoration sarcoma standard of care stem success synovial sarcoma targeted treatment transcriptome tumor tumor growth whole genome young adult

项目摘要

Project Summary: Synovial Sarcoma (SS) is driven by the SS18-SSX oncofusion, and SS18-SSX is the only reoccurring mutation in SS. SS normally metastasizes, resulting in a 15-year overall survival rate of less than 50%. This presents a particular problem as 1/3 of the patients that are diagnosed are under the age of 30. Polychemotherapy has a modest and variable effect on patients, immunotherapy activity is unremarkable, and there are currently no targeted therapy options to combat SS. SS18-SSX remains undruggable despite clearly being the driving event in these cancers. Thus, SS requires entirely new therapeutic approaches. In light of this, we tried to identify potential novel therapies by assessment of full genome short-interfering (si)-RNA screen data deposited into the DepMap database and subsequent cell culture experiments with SS cell lines and patient-derived xenograft cell cultures. Through these efforts, we have identified a clinically actionable synthetic lethality with SSX-SS18 in SS, namely disruption of the post-translational modification, SUMOylation. We find SS18-SSX activates the SUMOylation, and disruption of this pathway with the in-clinic SUMOylation inhibitor, TAK-981, disrupts SS18- SSX function, induces DNA damage and shrinks SS tumors in mice. Specific Aims Specific Aim 1: Test a diverse set of synovial sarcoma mouse models for efficacy and safety of SUMOylation inhibition Specific Aim 2: Investigate the relationship between SS18-SSX and the SUMOylated proteome in synovial sarcoma Study Design: We will further characterize the sensitivity of TAK-981 (alone and with chemotherapy and BRD9 degrader) in SS cell culture models including patient-derived organoids, and in vivo, in orthotopic patient-derived xenograft (PDX) models and genetic mouse models of SS. Through a series of proteomic and biochemical experiments, we will further categorize the mechanism of SS18-SSX-dependent toxicity stemming from disruption of the SUMOylation pathway. We will further examine the role of SS18-SSX in activating the SUMOylation pathway and the mechanism of action of TAK-981 in SS, which involves disrupting the SS18-SSX- ncBAF transcriptome. In all, we will attempt to gather the preclinical evidence supporting the translation of SUMOylation inhibitors to treat SS.

项目总结: