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

• 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
• 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

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）是一种侵袭性的儿科恶性肿瘤，起源于神经rest的细胞。 NB是 在最常见的小儿实体瘤中，有37％的患者被诊断为婴儿。高患者 风险NB的生存率为五年〜50％，尽管强化疗法可能会导致几种负面 结果，包括体重低，听力损失和神经损伤，死亡或其他后遗症。改进 针对这些小儿患者的治疗，需要新的方法。 SMARCA4（BRG1），主要ATPase 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 在晚期疾病中。不幸的是，针对SWI/SNF ATPase活动的适用性和 它在NB中的抑制作用尚未了解。我们已经采用了新的快速作用工具来定位 Smarca4在我们的初步数据中，该数据表明其失活会诱导NB的生存能力丧失 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，与复制应力或细胞周期失调一致。在这个 提案，我们寻求：（1）将SWI/SNF复合物的直接细胞周期特定效应绘制为DNA 可及性，转录和细胞死亡； （2）确定细胞周期放松管制和复制的机制 SWI/SNF抑制引起的应力； （3）在体外确定肿瘤特异性的协同药物组合和 在体内验证其功效。我们将使用目前在临床上使用的一组药物来治疗高风险NB， 在2D细胞，3D球体中检查与SWI/SNF抑制作用的治疗协同作用，并检查其组合 在严格的神经母细胞瘤小鼠模型中。我们确定组合疗法的策略 将由人类神经rest和周围神经元的柜台告知，以识别药物 对非肿瘤细胞的毒性最小的组合。我们的研究将确定主要途径 在与复制应力和细胞周期失调有关的NB中受SWI/SNF抑制作用的影响。我们的发现会 此外，可以鉴定和验证体内增强SWI/SNF阻滞的疗法。因为 小分子SWI/SNF抑制剂的耐受性很好，我们的翻译研究代表了一个重要的 临床前步骤可能会导致50％无反应的高危NB患者进行临床试验。