Mechanisms and small-molecule targeting of SWI/SNF activity in neuroblastoma

神经母细胞瘤中 SWI/SNF 活性的机制和小分子靶向

基本信息

批准号：
10501562
负责人：
Hamilton Courtney Hodges
金额：
$ 47.16万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2022-07-18 至 2027-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10501562
关键词：
3-Dimensional ATP phosphohydrolase Affect Animal Model Apoptosis Biological Assay Body Weight Cell Culture Techniques Cell Cycle Cell Cycle Deregulation Cell Cycle Progression Cell Death Cell Proliferation Cells Cessation of life Child Childhood Solid Neoplasm Clinical Clinical Trials Combined Modality Therapy Complex Conflict (Psychology)Cytogenetics DNA DNA Damage DNA replication fork Data Dependence Development Diagnosis Disease Drug Combinations Excision Fiber Gene Amplification Genetic Transcription Human Immunocompetent Impairment In Vitro Infant Kinetics Lead MYCN gene Malignant Childhood Neoplasm Malignant Neoplasms Maps Measures Modeling Mus Neural Crest Neural Crest Cell Neuroblastoma Neurons Oncogenic Outcome Output Pathway interactions Patients Peripheral Pharmaceutical Preparations Play Progression-Free Survivals Research Role S phase SMARCA4 gene SWI/SNF Family Complex Stains Survival Rate Therapeutic Toxic effect Treatment Efficacy Tumor Suppressor Proteins Validation Work addiction advanced disease chemotherapy counterscreen design effective therapy hearing impairment high risk improved in vivo inhibitor mouse model nerve damage neuroblastoma cell novel strategies novel therapeutic intervention pediatric patients pre-clinical programs replication stress response small molecule synergism temporal measurement tool translational study treatment duration tumor

项目摘要

Abstract Neuroblastoma (NB) is an aggressive pediatric malignancy originating from cells of neural crest origin. NB is among the most frequent pediatric solid tumors, with 37% of patients diagnosed as infants. Patients with high- risk NB have a five-year survival rate of ~50% despite intensive therapy that can cause several negative outcomes, including low body weight, hearing loss and nerve damage, death, or other sequelae. To improve treatment for these pediatric patients, new approaches are needed. SMARCA4 (BRG1), the primary ATPase of SWI/SNF complexes, has been identified as an oncogenic dependency for NB, with frequent gene amplifications in advanced disease. Unfortunately, the suitability of targeting SWI/SNF ATPase activity and the mechanisms of its inhibition in NB have remained poorly understood. We have employed new fast-acting tools to target SMARCA4 in our preliminary data, which revealed that its inactivation induces profound loss of viability of NB cells independently of MYCN or other cytogenetic features. We have found that inactivation of SMARCA4 induces cell death near the G1-S boundary, consistent with replication stress or cell-cycle dysregulation. In this proposal, we seek to: (1) Map the direct cell cycle-specific effects of SWI/SNF complexes towards DNA accessibility, transcription, and cell death; (2) Identify the mechanisms of cell cycle deregulation and replication stress induced by SWI/SNF inhibition; and (3) Identify tumor-specific synergistic drug combinations in vitro and validate their efficacy in vivo. We will employ a panel of drugs currently used clinically to treat high-risk NB, to examine therapeutic synergy with SWI/SNF inhibition in 2D cells, 3D spheroids, and examine their combination in a rigorous immune-competent mouse model of neuroblastoma. Our strategy to identify combination therapies will be informed by a counter-screen with human neural crest and peripheral neurons, to identify drug combinations that show minimal toxicity to non-tumor cells. Our studies will identify the principal pathways influenced by SWI/SNF inhibition in NB related to replication stress and cell cycle dysregulation. Our findings will furthermore enable identification and validation of therapies that potentiate SWI/SNF blockade in vivo. Because small-molecule SWI/SNF inhibitors are well tolerated by mice, our translational studies represent an important preclinical step that may lead to clinical trials for the 50% of unresponsive high-risk NB patients.

抽象的神经母细胞瘤（NB）是一种源自神经嵴细胞的侵袭性儿科恶性肿瘤。注意是是最常见的儿科实体瘤之一，37% 的患者在婴儿时期被诊断出来。患有高尽管强化治疗可能会导致一些负面影响，但风险 NB 的五年生存率约为 50% 结果，包括体重减轻、听力损失和神经损伤、死亡或其他后遗症。改善对于这些儿科患者的治疗，需要新的方法。 SMARCA4 (BRG1)，初级 ATP 酶 SWI/SNF 复合物已被确定为 NB 的致癌依赖性，具有频繁的基因扩增在疾病晚期。不幸的是，针对 SWI/SNF ATP 酶活性的适用性及其机制其对 NB 的抑制作用仍知之甚少。我们采用了新的快速作用工具来瞄准我们初步数据中的 SMARCA4，表明其失活会导致 NB 活力严重丧失细胞独立于 MYCN 或其他细胞遗传学特征。我们发现 SMARCA4 失活诱导 G1-S 边界附近的细胞死亡，与复制应激或细胞周期失调一致。在这个根据提案，我们寻求：（1）绘制 SWI/SNF 复合物对 DNA 的直接细胞周期特异性效应可及性、转录和细胞死亡； (2) 识别细胞周期失调和复制的机制 SWI/SNF 抑制引起的应激； (3) 体外鉴定肿瘤特异性协同药物组合验证它们的体内功效。我们将采用目前临床上用于治疗高危 NB 的一组药物，检查 2D 细胞、3D 球体中 SWI/SNF 抑制的治疗协同作用，并检查它们的组合在严格的免疫活性小鼠神经母细胞瘤模型中。我们确定联合疗法的策略将通过带有人类神经嵴和周围神经元的反屏幕通知，识别药物对非肿瘤细胞显示出最小毒性的组合。我们的研究将确定主要途径 NB 中受 SWI/SNF 抑制的影响与复制应激和细胞周期失调有关。我们的研究结果将此外，还能够识别和验证增强体内 SWI/SNF 阻断的疗法。因为小分子 SWI/SNF 抑制剂对小鼠具有良好的耐受性，我们的转化研究代表了重要的临床前步骤可能会导致对 50% 无反应的高危 NB 患者进行临床试验。