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

• 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
• 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

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.

项目概要： 滑膜肉瘤（SS）是由SS 18-SSX癌融合驱动的，SS 18-SSX是唯一的复发突变 在SS。SS通常转移，导致15年总生存率低于50%。这提出了一个 这是一个特别的问题，因为被诊断的患者中有三分之一年龄在30岁以下。综合化疗具有 对患者的影响温和且可变，免疫治疗活性不显著，目前没有 有针对性的治疗方案来对抗SS。SS 18-SSX尽管明显是驱动事件，但仍然不可接受 在这些癌症中。因此，SS需要全新的治疗方法。有鉴于此，我们试图找出 潜在的新疗法，通过评估全基因组短干扰（si）-RNA筛选数据存入 DepMap数据库和随后的SS细胞系和患者来源的异种移植细胞的细胞培养实验 cultures.通过这些努力，我们已经确定了SSX-SS 18在SS中的临床可操作的合成致死性， 即翻译后修饰SUMO化的破坏。我们发现SS 18-SSX激活了 SUMO化，以及使用临床SUMO化抑制剂TAK-981破坏该途径， SSX功能，诱导DNA损伤和缩小小鼠SS肿瘤。 具体目标 具体目标1：测试一组不同的滑膜肉瘤小鼠模型的SUMO化的有效性和安全性 抑制 具体目的2：研究SS 18-SSX与滑膜中SUMO化蛋白质组的关系 肉瘤 研究设计：我们将进一步表征TAK-981（单独给药以及与化疗和BRD联合给药）的敏感性9 降解剂）在SS细胞培养模型中，包括患者来源的类器官，以及在体内，在原位患者来源的类器官中， 异种移植（PDX）模型和SS的遗传小鼠模型。通过一系列的蛋白质组学和生物化学 在实验中，我们将进一步分类SS 18-SSX依赖性毒性的机制， SUMO化途径的破坏。我们将进一步研究SS 18-SSX在激活 SUMO化途径和TAK-981在SS中的作用机制，包括破坏SS 18-SSX- ncBAF转录组。总之，我们将试图收集支持翻译的临床前证据， SUMO化抑制剂治疗SS。