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Clinical & Mechanistic underpinnings to reducing PAX:FOXO1 for alveolar rhabdomyosarcoma

临床

基本信息

批准号：
10182958
负责人：
CHARLES KELLER
金额：
$ 30.38万
依托单位：
CHILDREN'S CANCER THERAPY DEVELOP/INST
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-05-14 至 2026-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10182958
关键词：
ATP phosphohydrolase Address Alveolar Rhabdomyosarcoma Automobile Driving Biology Bromodomain Catalytic Domain Cell Maintenance Cell Survival Cellular Stress Chemotherapy and/or radiation Childhood Clinical Clinical Trials Clinical Trials Cooperative Group Complex Cyclophosphamide DNA Disease Dose Down-Regulation Doxorubicin Drops Evolution FOXO1A gene Gene Fusion Genes Genetic Grant HDAC3 gene Histone Deacetylase Histone Deacetylase Inhibitor Human Implant Maintenance Malignant Neoplasms Mediating Messenger RNA MicroRNAs Mitotic Molecular Mus Mutation Oncogenes Outcome PAX3 gene Patients Pediatric Oncology Group Pharmaceutical Preparations Pharmacology Phase Phase I Clinical Trials Phase II Clinical Trials Predisposition Process Proteins Publishing Recurrence Relapse Reporting Repression Resistance Rhabdomyosarcoma Role SMARCA2 gene SMARCA4 gene SWI/SNF Family Complex Safety Science Signal Transduction Testing Treatment Failure Vincristine Work biological adaptation to stress chemotherapy comparative efficacy efficacy testing epigenetic regulation epigenetic silencing evidence base improved insight knock-down loss of function malignant breast neoplasm malignant muscle neoplasm neoplastic cell novel response small hairpin RNA soft tissue synergism therapeutic target therapy resistant tool tumor

项目摘要

SUMMARY The childhood muscle cancer alveolar rhabdomyosarcoma (ARMS) is generally not survivable when metastatic. However, ARMS does usually respond clinically to chemotherapy initially. With respect to the cause of recurrences, clinicians observe that the PAX3:FOXO1 oncogene present in most ARMS cases mediates treatment resistance, causing a 45% drop in 10-year survival. In explanation, we reported that PAX3:FOXO1 facilitates G2/M checkpoint adaptation (tolerance of DNA breaks & mitotic catastrophe). Thus, the driving clinical challenge is to overcome recurrence by counteracting PAX3:FOXO1. We published that PAX3:FOXO1 can be pharmacologically silenced by entinostat, a novel histone deacetylase inhibitor. We find entinostat dramatically improves ARMS sensitivity to frontline chemotherapy. Mechanistically, our recently published studies implicate an HDAC3 – SMARCA4 – miR-27a – PAX3:FOXO1 regulatory circuitry in ARMS. In parallel we have uncovered that SMARCA4 expression is uniquely elevated in fusion positive ARMS, and that ARMS-selective SMARCA4 expression is a pivotal long-term susceptibility in tumor cell survival. These results point to SMARCA4 having a key role in fusion positive ARMS – controlling PAX3:FOXO1 and chemotherapy sensitivity in the short-term and tumor cell maintenance long-term. We hypothesize that PAX3:FOXO1+ ARMS can be made more chemosensitive at relapse and less likely to recur by epigenetically silencing PAX3:FOXO1. Thus, our aims are to: (1) Delineate the atypical role of SMARCA4 as an oncogene in ARMS via the SWI/SNF BAF complex, and (2) Test efficacy of direct PAX3:FOXO1 inhibition versus upstream SMARCA4/A2 inhibition versus entinostat when combined with relapse chemotherapy and non-chemotherapy agents. From these results, we hope to understand rhabdomyosarcoma molecular underpinnings.

总结儿童肌肉癌腺泡状横纹肌肉瘤（ARMS）转移时通常无法存活。然而，ARMS通常在临床上对化疗有反应。关于临床医生观察到，大多数ARMS病例中存在的PAX 3：FOXO 1癌基因介导了复发治疗抵抗，导致10年生存率下降45%。在解释中，我们报道了PAX 3：FOXO 1 促进G2/M检查点适应（DNA断裂和有丝分裂灾难的耐受性）。因此，驱动临床挑战是通过抵消PAX 3：FOXO 1来克服复发。我们发表了PAX 3：FOXO 1可以被恩替司他是一种新型的组蛋白去乙酰化酶抑制剂。我们发现恩替司他提高ARMS对一线化疗的敏感性。从机制上讲，我们最近发表的研究表明， ARMS中的HDAC 3-SMARCA 4- miR-27 a-PAX 3：FOXO 1调节回路。与此同时，我们发现 SMARCA 4表达在融合阳性ARMS中独特地升高，且ARMS选择性SMARCA 4 表达是肿瘤细胞存活的关键长期易感性。这些结果表明SMARCA 4具有在融合阳性ARMS中的关键作用-控制PAX 3：FOXO 1和短期化疗敏感性，肿瘤细胞长期维持。我们假设PAX 3：FOXO 1 + ARMS可以被更多地在复发时具有化学敏感性，并且通过表观遗传学沉默PAX 3：FOXO 1而不太可能复发。因此，我们的目标是目的：（1）通过SWI/SNF BAF复合物阐明SMARCA 4作为癌基因在ARMS中的非典型作用，和（2）直接PAX 3：FOXO 1抑制相对于上游SMARCA 4/A2抑制相对于上游SMARCA 4/A2抑制的测试功效。恩替司他与复发化疗和非化疗药物联合使用。从这些结果，我们希望了解横纹肌肉瘤的分子基础。