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

临床

基本信息

批准号：
10405632
负责人：
CHARLES KELLER
金额：
$ 29.77万
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/10405632
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.

概括儿童肌肉癌肺泡横纹肌肉瘤（ARMS）在转移时通常无法存活。然而，就其病因而言，ARMS 通常在临床上最初对化疗有反应。复发，观察到大多数 ARMS 病例中存在的 PAX3:FOXO1 癌基因介导治疗耐药，导致 10 年生存率下降 45% 在解释中，我们报道了 PAX3:FOXO1。促进 G2/M 检查点适应（DNA 断裂和有丝分裂灾难的耐受性），从而推动临床。挑战是通过抵消 PAX3:FOXO1 来克服复发。我们发表了 PAX3:FOXO1 可以被克服。恩替司他（一种新型组蛋白脱乙酰酶抑制剂）在药理学上沉默。我们发现恩替司他具有显着的沉默作用。我们最近发表的研究表明，从机制上讲，ARMS 可以提高对一线化疗的敏感性。与此同时，我们还发现了 ARMS 中的 HDAC3 – SMARCA4 – miR-27a – PAX3:FOXO1 调节电路。 SMARCA4 表达在融合阳性 ARMS 中独特升高，并且 ARMS 选择性 SMARCA4 这些结果表明 SMARCA4 的表达是肿瘤细胞存活的关键长期易感性。融合阳性 ARMS 中的关键作用 - 控制 PAX3:FOXO1 和短期和短期内的化疗敏感性我们勇敢地认为PAX3:FOXO1+ ARMS可以做更多。通过表观遗传沉默 PAX3:FOXO1，复发时对化学敏感，并且复发的可能性较小。因此，我们的目标是。 (1) 通过 SWI/SNF BAF 复合体描述 SMARCA4 作为 ARMS 癌基因的非典型作用， (2) 测试直接 PAX3:FOXO1 抑制与上游 SMARCA4/A2 抑制与上游 SMARCA4/A2 抑制的功效恩替司他与复发化疗和非化疗药物联合使用。通过研究结果，我们希望了解横纹肌肉瘤的分子基础。