Characterizing Chromatin Remodeling Mechanisms of Chemo-Sensitivity and Resistance in Pediatric Solid Tumors

表征儿科实体瘤化疗敏感性和耐药性的染色质重塑机制

• 批准号: 10369901
• 负责人: Maggie Chasse
• 金额: $ 9.55万
• 依托单位: BOSTON CHILDREN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10369901
• 关键词: Characterizing; Chromatin; Remodeling; Mechanisms; Chemo

PROJECT SUMMARY Despite the known roles of chromatin remodeling complexes in driving more than 20% of human cancer, the role of chromatin remodeling complexes in conferring therapeutic response in pediatric solid tumors is much less understood. Rhabdoid tumor requires residual SWI/SNF activity for transformation and progression. However, it is not known if SWI/SNF and its effect on the underlying epigenome is therapeutically targetable and if a compound targeting this complex will be successful. Furthermore, SWI/SNF has been implicated in epigenetic mechanisms of resistance suggesting this complex may be able to both confer sensitivity and resistance depending on the cancer context. Fusion positive alveolar rhabdomyosarcoma (ARMS) gains chemo-resistance without the simultaneous gain of mutations to drive this resistance. These data indicate ARMS relapse may be driven by epigenetic mechanisms. Therefore, the overall objective of this study is to define the role of chromatin structure in conferring therapeutic sensitivity in rhabdoid tumor (Aim 1) and resistance in rhabdomyosarcoma (Aim 2). I have identified mithramycin as a SWI/SNF inhibitor that induces epigenetic reprogramming and durable tumor regression in rhabdoid tumor. A consequence of mithramycin treatment is amplification of H3K27me3, a novel therapeutic vulnerability as well as the restoration of chemosensitivity. The overall goal of the F99 phase (Aim 1) is to identify synthetic lethalities that arise from SWI/SNF inhibition. Specifically, aim 1.1 will define inhibition of H3K27me3 histone demethylases KDM6A/6B as a therapeutic vulnerability in rhabdoid tumor. Aim 1.2 will define the mechanism of mithramycin-dependent chemosensitivity. These goals will build advanced expertise in mechanistic pharmacology, high-throughput sequencing, and in vivo modeling of combination therapies. In contrast to RT which is known to be chemo-refractory, alveolar rhabdomyosarcoma is initially responsive to chemotherapy before gaining resistance. Therefore, the K00 phase of this fellowship (Aim 2) will define the role of chromatin remodeling in fusion positive alveolar rhabdomyosarcoma therapeutic resistance (ARMS). Aim 2.1 will identify the chromatin remodeler that coordinates with PAX3/7-FOXO1, the oncogenic transcription factor that drives ARMS transformation and progression. Aim 2.2 will profile chromatin remodeling during the establishment of chemoresistance in an established ARMS mouse model. This phase will expand expertise in genomic approaches to include single-cell genomics and in vivo modeling to include transgenic models. In summary, this study addresses the need for a mechanistic investigation into the role of chromatin remodeling in driving therapeutic response in pediatric solid tumors. Data and training acquired in this phase will prepare me for a career exploring epigenetic mechanisms of therapeutic resistance in pediatric sarcomas.

项目摘要 尽管已知染色质重塑复合物在驱动超过20%的人类癌症中的作用， 染色质重塑复合物在儿科实体瘤治疗反应中的作用 更少被理解。横纹肌样瘤需要残留的SWI/SNF活性来转化和进展。 然而，尚不清楚SWI/SNF及其对潜在表观基因组的作用是否具有治疗靶向性 以及针对这种复合物的化合物是否会成功。此外，SWI/SNF还参与了 抗性的表观遗传机制表明这种复合物可能既能赋予敏感性， 耐药性取决于癌症背景。融合阳性腺泡状横纹肌肉瘤（ARMS） 化学抗性，而不同时获得突变来驱动这种抗性。这些数据表明 ARMS复发可能由表观遗传机制驱动。因此，本研究的总体目标是 确定染色质结构在横纹肌样瘤治疗敏感性中的作用（Aim 1）， 横纹肌肉瘤耐药（Aim 2）。 我已经确定了光神霉素作为SWI/SNF抑制剂，诱导表观遗传重编程和持久的肿瘤 横纹肌样瘤的消退。光神霉素处理的结果是H3 K27 me 3的扩增，H3 K27 me 3是一种新的 治疗脆弱性以及化学敏感性的恢复。F99阶段的总体目标（Aim 1)是鉴定由SWI/SNF抑制引起的合成致死性。具体而言，目标1.1将定义抑制 H3 K27 me 3组蛋白去甲基化酶KDM 6A/6 B作为横纹肌样瘤的治疗弱点。目标1.2将 定义了米曲霉素依赖性化学敏感性的机制。这些目标将建立先进的专业知识 在机制药理学、高通量测序和联合治疗的体内建模方面。在 与已知的化疗难治性RT相反，腺泡状横纹肌肉瘤最初对化疗敏感， 在获得耐药性之前进行化疗。因此，本奖学金的K 00阶段（目标2）将定义 染色质重塑在融合阳性腺泡状横纹肌肉瘤治疗抵抗（ARMS）中的作用。 目的2.1将鉴定与PAX 3/7-FOXO 1（致癌基因）协调的染色质重塑物。 转录因子驱动ARMS转化和进展。Aim 2.2将描述染色质重塑 在已建立的ARMS小鼠模型中建立化学抗性期间。这一阶段将扩大 在基因组学方法，包括单细胞基因组学和体内建模，包括转基因 模型 总之，这项研究解决了需要一个机制调查的作用，染色质 重塑驱动儿科实体瘤的治疗反应。本阶段获得的数据和培训 将为我的职业生涯做好准备，探索儿科肉瘤治疗耐药性的表观遗传机制。